Alkynl and azido-substituted 4-anilinoquinazolines

ABSTRACT

The invention relates to compounds of the formula 
                 
 
and to pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , n and m are as defined herein. The compounds of formula I are useful in the treatment of hyperproliferative diseases, such as cancer. The invention further relates to processes of making the compounds of formula I and to methods of using such compounds in the treatment of hyperproliferative diseases.

This application is a continuation-in-part of PCT internationalapplication number PCT/IB95/00436, filed Jun. 6, 1995, which designatesthe United States.

BACKGROUND OF THE INVENTION

This invention relates to 4-(substituted phenylamino) quinazolinederivatives which are useful in the treatment of hyperproliferativediseases, such as cancers, in mammals.

Many of the current treatment regimes for cancer utilize compounds whichinhibit DNA synthesis. Such compounds are toxic to cells generally buttheir toxic effect on the rapidly dividing tumor cells can bebeneficial. Alternative approaches to anti-cancer agents which act bymechanisms other than the inhibition of DNA synthesis have been exploredin order to enhance the selectivity of action against cancer cells.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e. a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins which are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are large enzymes which span the cell membraneand possess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion which functions as a kinase to phosphorylate specific tyrosineresidues in proteins and hence to influence cell proliferation. It isknown that such kinases are frequently aberrantly expressed in commonhuman cancers such as breast cancer, gastrointestinal cancer such ascolon, rectal or stomach cancer, leukemia, and ovarian, bronchial orpancreatic cancer. It has also been shown that epidermal growth factorreceptor (EGFR) which possesses tyrosine kinase activity is mutatedand/or overexpressed in many human cancers such as brain, lung, squamouscell, bladder, gastric, breast, head and neck, oesophageal,gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosinekinases are useful as a selective inhibitors of the growth of mammaliancancer cells. For example, erbstatin, a tyrosine kinase inhibitorselectively attenuates the growth in athymic nude mice of a transplantedhuman mammary carcinoma which expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of anothercarcinoma which does not express the EGF receptor.

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties. More recentlyfive European patent publications, namely EP 0 566 226 A1, EP 0 602 851A1, EP 0 635 507 A1, EP 0 635 498 A1 and EP 0 520 722 A1 have disclosedthat certain quinazoline derivatives possess anti-cancer propertieswhich result from their tyrosine kinase inhibitory properties. Also PCTpublication WO 92/20642 discloses bis-mono and bicyclic aryl andheteroaryl compounds as tyrosine kinase inhibitors.

Although the anti-cancer compounds described above make a significantcontribution to the art there is a continuing search in this field ofart for improved anti-cancer pharmaceuticals.

SUMMARY OF THE INVENTION

This invention relates to compounds of the formula

and to pharmaceutically acceptable salts and prodrugs thereof, wherein:

-   -   m is 1, 2, or 3;    -   each R¹ is independently selected from the group consisting of        hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro,        guanidino, ureido, cyano, trifluoromethyl, and -(C₁-C₄        alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;    -   or each R¹ is independently selected from R⁹ and (C₁-C₄)-alkyl        substituted by cyano, wherein R⁹ is selected from the group        consisting of R⁵, —OR⁶, —NR⁶R⁶, —C(O)R⁷, —NHOR⁵, —OC(O)R⁶,        cyano, A and —YR⁵; R⁵ is C₁-C₄ alkyl; R⁶ is independently        hydrogen or R⁵; R⁷ is R⁵, —OR⁶ or —NR⁶R⁶; A is selected from        piperidino, morpholino, pyrrolidino, 4-R⁶-piperazin-1-yl,        imidazol-1-yl, 4-pyridon-1-yl, -(C₁-C₄ alkylene)(CO₂H), phenoxy,        phenyl, phenylsulfanyl, C₂-C₄ alkenyl, and -(C₁-C₄        alkylene)C(O)NR⁶R⁶; and Y is S, SO, or SO₂; wherein the alkyl        moieties in R⁵, —OR⁶ and —NR⁶R⁶ are optionally substituted by        one to three substituents independently selected from halo and        R⁹, and wherein the alkyl moieties of said optional substituents        are optionally substituted by halo or R⁹, with the proviso that        two heteroatoms are not attached to the same carbon atom, and        with the further proviso that no more than three R⁹ groups may        comprise a single R¹ group;    -   or each R¹ is independently selected from —NHSO₂R⁵,        phthalimido-(C₁-C₄)-alkylsulfonylamino, benzamido,        benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl,        2,5-dioxopyrrolidin-1-yl, and R¹⁰-(C₂-C₄)-alkanoylamino wherein        R¹⁰ is selected from halo, —OR⁶, C₂-C₄ alkanoyloxy, —C(O)R⁷, and        —NR⁶R⁶; and wherein the foregoing R¹ groups are optionally        substituted by 1 or 2 substituents independently selected from        halo, C₁-C₄ alkyl, cyano, methanesulfonyl and C₁-C₄ alkoxy;    -   or two R¹ groups are taken together with the carbons to which        they are attached to form a 5-8 membered ring that includes 1 or        2 heteroatoms selected from O, S and N;    -   R² is hydrogen or C₁-C₆ alkyl optionally substituted by 1 to 3        substituents independently selected from halo, C₁-C₄ alkoxy,        —NR⁶R⁶, and —SO₂R⁵;    -   n is 1 or 2 and each R³ is independently selected from hydrogen,        halo, hydroxy, C₁-C₆ alkyl, —NR⁶R⁶, and C₁-C₄ alkoxy, wherein        the alkyl moieties of said R³ groups are optionally substituted        by 1 to 3 substituents independently selected from halo, C₁-C₄        alkoxy, —NR⁶R⁶, and —SO₂R⁵; and,    -   R⁴ is azido or -(ethynyl)-R¹¹ wherein R¹¹ is hydrogen or C₁-C₆        alkyl optionally substituted by hydroxy, —OR⁶, or —NR⁶R⁶.

Preferred compounds of formula I include those wherein R² is hydrogenand R⁴ is -(ethynyl)-R¹¹.

Other preferred compounds of formula I include those wherein m is 1 or2;

-   -   each R¹ is independently selected from the group consisting of        hydrogen, hydroxy, hydroxyamino, carboxy, nitro, carbamoyl,        ureido, R⁵ optionally substituted with halo, —OR⁶, carboxy,        —C(O)NR⁶R⁶, A or —NR⁶R⁶; —OR⁵ optionally substituted with halo,        —OR⁶, —OC(O)R⁶, —NR⁶R⁶, or A; —NR⁶R⁶, —C(O)R⁶ R⁵, —SR⁵,        phenyl-(C₂-C₄)-alkoxy, cyano, phenyl; —NHR⁵ optionally        substituted with halo or R⁹ wherein said R⁹ is optionally        substituted by R⁹; —NHOR⁵, —SR⁵, C₁-C₄ alkylsulfonylamino,        phthalimido-(C₁-C₄)-alkylsulfonylamino, 3-phenylureido,        2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl,        halo-(C₂-C₄)-alkanoylamino, hydroxy-(C₂-C₄)-alkanoylamino,        (C₂-C₄)-alkanoyloxy-(C₂-C₄)-alkanoylamino,        (C₁-C₄)-alkoxy-(C₂-C₄)-alkanoylamino,        (C₁-C₄)-alkoxycarbonyl-(C₂-C₄)-alkanoylamino,        carbamoyl-(C₂-C₄)-alkanoylamino,        N-(C₁-C₄)-alkylcarbamoyl-(C₂-C₄)-alkanoylamino,        N,N-di-[(C₁-C₄)-alkyl]carbamoyl-(C₂-C₄)-alkanoylamino,        amino-(C₂-C₄)-alkanoylamino,        (C₁-C₄)-alkyl-amino-(C₂-C₄)-alkanoylamino, and        di-(C₁-C₄)-alkyl-amino-(C₂-C₄)-alkanoylamino, and wherein said        phenyl or phenoxy or anilino substituent in the foregoing R¹        groups is optionally substituted with one or two substituents        independently selected from halo, C₁-C₄ alkyl and C₁-C₄ alkoxy;    -   each R³ is independently selected from hydrogen, methyl, ethyl,        amino, halo and hydroxy; and,    -   R⁴ is ethynyl.

Other preferred compounds of formula I include those wherein each R¹ isindependently selected from hydrogen, hydroxy, hydroxyamino, nitro,carbamoyl, ureido, R⁵ optionally substituted with halo, —OR⁶, carboxy,or —C(O)NH₂; —OR⁵ optionally substituted with halo, —OR⁶, —OC(O)R⁶,—NR⁶R⁶, or A; —NR⁶R⁶, —C(O)NR⁶R⁶, —SR⁵, phenyl-(C₂-C₄)-alkoxy whereinsaid phenyl moiety is optionally substituted with 1 or 2 substituentsindependently selected from halo, R⁵ or —OR⁵.

Other preferred compounds of formula I include those wherein R² ishydrogen and R⁴ is azido.

Other preferred compounds of formula I include those wherein R³ is haloand R¹ is hydrogen or —OR⁵.

Other preferred compounds of formula I include those wherein R¹ ismethoxy.

Specific preferred compounds of formula I include the following:

-   (6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6,7-dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine;-   [3-(2′-(aminomethyl)-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine;-   (3-ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine;-   (6,7-dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine;-   (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine;-   (6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl)-amine;-   (3-ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amine;-   (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-6-methylphenyl)-amine;-   (3-ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine;-   (3-ethynylphenyl)-[6-(4′-toluenesulfonylamino)quinazolin-4-yl]-amine;-   (3-ethynylphenyl)-{6-[2′-phthalimido-eth-1′-yl-sulfonylamino]quinazolin-4-yl}-amine;-   (3-ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine;-   (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine;-   (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;-   [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine;-   (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;-   (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;-   (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;-   (3-ethynylphenyl)-(6-methansulfonyl-quinazolin-4-yl)-amine;-   (6-ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine-   (6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;-   (6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1′-yl)-phenyl]-amine;-   [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amine;-   [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amine;-   [6,7-bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;-   [6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;-   [6,7-bis-(2-acetoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;-   2-[4-(3-ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanol;-   [6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;-   [7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;-   [7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;-   2-[4-(3-ethynyl-phenylamino)-6-(2-hydroxy-ethoxy)-quinazolin-7-yloxy]-ethanol;-   2-[4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanol;-   2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol;-   [6-(2-acetoxy-ethoxy)-7-(2    -methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;-   (3-ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine;-   (3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl)-ethoxy)-quinazolin-4-yl]-amine;-   (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;-   (6,7-dibutoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;-   (6,7-diisopropoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;-   (6,7-diethoxyquinazolin-1-yl)-(3-ethynyl-2-methyl-phenyl)-amine;-   [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynyl-2-methyl-phenyl)-amine;-   (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;-   [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;    and-   2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol.

Other specific preferred compounds of formula I include the following:

-   (6,7-dipropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;-   (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-phenyl)-amine;-   (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;-   (6,7-diethoxy-quinazolin-4-yl)-(5-ethynyl-2-methyl-phenyl)-amine;-   (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-methyl-phenyl)-amine;-   (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;-   (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylmethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylmethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;-   (6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;    and-   (6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine.

Other specific preferred compounds of formula I include the following:

-   (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;-   (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;-   [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;-   [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;-   (6,7-dimethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;-   (3-ethynylphenyl)-(6-methanesulfonylamino-quinazolin-1-yl)-amine;    and,-   (6-amino-quinazolin-1-yl)-(3-ethynylphenyl)-amine.

The invention further relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically-effective amount of the compound of claim 1 and apharmaceutically acceptable carrier.

The invention further relates to a method of treating ahyperproliferative disorder in a mammal which comprises administering tosaid mammal a therapeutically-effective amount of the compound of claim1.

In a preferred embodiment, the method of treating hyperproliferativedisorders includes those wherein said hyperproliferative disorder iscancer.

In another preferred embodiment, the method of treatinghyperproliferative disorders includes those wherein saidhyperproliferative disorder is said cancer is brain, lung, squamouscell, bladder, gastric, pancreatic, breast, head, neck, oesophageal,gynecological or thyroid cancer.

In another preferred embodiment, the method of treatinghyperproliferative disorders includes those wherein saidhyperproliferative disorder is noncancerous.

In another preferred embodiment, the method of treatinghyperproliferative disorders includes those wherein saidhyperproliferative disorder is a benign hyperplasia of the skin orprostate.

The invention further relates to a process for preparing a compound ofthe formula

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   -   m is 1, 2, or 3;    -   each R¹ is independently selected from the group consisting of        hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro,        guanidino, ureido, cyano, trifluoromethyl, and -(C₁-C₄        alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;    -   or each R¹ is independently selected from R⁹ and (C₁-C₄)-alkyl        substituted by cyano, wherein R⁹ is selected from the group        consisting of R⁵, —OR⁶, —NR⁶R⁶, —C(O)R⁷, —NHOR⁵, —OC(O)R⁶,        cyano, A and —YR⁵; R⁵ is C₁-C₄ alkyl; R⁶ is independently        hydrogen or R⁵; R⁷ is R⁵, —OR⁶ or —NR⁶R⁶; A is selected from        piperidino, morpholino, pyrrolidino, 4-R⁶-piperazin-1-yl,        imidazol-1-yl, 4-pyridon-1-yl, -(C₁-C₄ alkylene)(CO₂H), phenoxy,        phenyl, phenylsulfanyl, C₂-C₄ alkenyl, and -(C₁-C₄        alkylene)C(O)NR⁶R⁶; and Y is S, SO, or SO₂; wherein the alkyl        moieties in R⁵, —OR⁶ and —NR⁶R⁶ are optionally substituted by        one to three substituents independently selected from halo and        R⁹, and wherein the alkyl moieties of said optional substituents        are optionally substituted by halo or R⁹, with the proviso that        two heteroatoms are not attached to the same carbon atom, and        with the further proviso that no more than three R⁹ groups may        comprise a single R¹ group;    -   or each R¹ is independently selected from —NHSO₂R⁵,        phthalimido-(C₁-C₄)-alkylsulfonylamino, benzamido,        benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl,        2,5-dioxopyrrolidin-1-yl, and R¹⁰-(C₂-C₄)-alkanoylamino wherein        R¹⁰ is selected from halo, —OR⁶, C₂-C₄ alkanoyloxy, —C(O)R⁷, and        —NR⁶R⁶; and wherein the foregoing R¹ groups are optionally        substituted by 1 or 2 substituents independently selected from        halo, C₁-C₄ alkyl, cyano, methanesulfonyl and C₁-C₄ alkoxy;    -   or two R¹ groups are taken together with the carbons to which        they are attached to form a 5-8 membered ring that includes 1 or        2 heteroatoms selected from O, S and N;    -   R² is hydrogen or C₁-C₆ alkyl optionally substituted by 1 to 3        substituents independently selected from halo, C₁-C₄ alkoxy,        —NR⁶R⁶, and —SO₂R⁵;    -   n is 1 or 2 and each R³ is independently selected from hydrogen,        halo, hydroxy, C₁-C₆ alkyl, —NR⁶R⁶, and C₁-C₄ alkoxy, wherein        the alkyl moieties of said R³ groups are optionally substituted        by 1 to 3 substituents independently selected from halo, C₁-C₄        alkoxy, —NR⁶R⁶, and —SO₂R⁵; and,    -   R⁴ is azido or -(ethynyl)-R¹¹ wherein R¹¹ is hydrogen or C₁-C₆        alkyl optionally substituted by hydroxy, —OR⁶, or —NR⁶R⁶; which        comprises        -   a) treating a compound of the formula    -   wherein R¹ and m are as defined above, with CCl₄ and        (C₆-C₁₀aryl)₃P, optionally supported on an inert polymer,        wherein the aryl moieties of said (C₆-C₁₀aryl)₃P are optionally        substituted by C₁-C₆ alkyl; and        -   b) treating the product of step a) with a compound of the            formula    -   wherein R², R³ and n are as defined above, and J is Y or R⁴,        wherein R⁴ is as defined above and wherein Y is NH₂, Br, I or        trifluoromethanesulfonyloxy, with the proviso that when J is Y        then the product of step b) must further be treated with an        alkyne where Y is Br, I or trifluoromethanesulfonyloxy, or an        azide where Y is NH₂.

Preferred processes for preparing the compound of formula I includethose wherein each aryl group is selected from phenyl, naphth-1-yl andnaphth-2-yl.

Other preferred processes for preparing the compound of formula Iinclude those wherein each Ar in (C₆-C₁₀aryl)₃P is phenyl.

Other preferred processes for preparing the compound of formula Iinclude those wherein said (C₆-C₁₀aryl)₃P is supported on an inertpolymer.

Other preferred processes for preparing the compound of formula Iinclude those wherein said inert polymer is adivinylbenzene-cross-linked polymer of styrene.

The term “halo”, as used herein, unless otherwise indicated, meanschloro, bromo, iodo, or fluoro.

The term “alkyl”, as used herein, unless otherwise indicated, meansstraight chained, cyclic or branched, saturated or unsaturatedhydrocarbon moiety with the proviso that said alkyl must comprise threeor more carbon atoms if it is branched or cyclic.

As used herein, the expression “reaction-inert solvent” refers to asolvent which does not interact with starting materials, reagents,intermediates or products in a manner which adversely affects the yieldof the desired product.

Other features and advantages will be apparent from the specificationand claims which describe the invention.

DETAILED DESCRIPTION OF THE INVENTION

The Formula I compounds, pharmaceutically acceptable salts and prodrugsthereof (hereafter the active compounds) may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds.

In general the active compounds may be made from the appropriatelysubstituted quinazoline using the appropriately substituted amine.

As shown in the Scheme the appropriate 4-substituted quinazoline 2wherein X is a suitable displaceable leaving group such as halo,aryloxy, alkylsulfinyl, alkylsulfonyl such astrifluoromethanesulfonyloxy, arylsulfinyl, arylsulfonyl, siloxy, cyano,pyrazolo, triazolo or tetrazolo, preferably a 4-chloroquinazoline, isreacted with the appropriate amine or amine hydrochloride 4 or 5,wherein R⁴ is as described above and Y is Br, I, ortrifluoromethane-sulfonyloxy in a solvent such as a (C₁-C₆)alcohol,dimethylformamide (DMF), N-methylpyrrolidin-2-one, chloroform,acetonitrile, tetrahydrofuran (THF), 1-4 dioxane, pyridine or otheraprotic solvent. The reaction may be effected in the presence of a base,preferably an alkali or alkaline earth metal carbonate or hydroxide or atertiary amine base, such as pyridine, 2,6-lutidine, collidine,N-methyl-morpholine, triethylamine, 4-dimethylamino-pyridine orN,N-dimethylaniline. These bases are hereinafter refered to as suitablebases. The reaction mixture is maintained at a temperature from aboutambient to about the reflux temperature of the solvent, preferably fromabout 35° C. to about reflux, until substantially no remaining4-haloquinazoline can be detected, typically about 2 to about 24 hours.Preferably, the reaction is performed under an inert atmosphere such asdry nitrogen.

Generally the reactants are combined stoichiometrically. When an aminebase is used for those compounds where a salt (typically the HCl salt)of an amine 4 or 5 is used, it is preferable to use excess amine base,generally an extra equivalent of amine base. (Alternatively, if an aminebase is not used an excess of the amine 4 or 5 may be used).

For those compounds where a sterically hindered amine 4 (such as a2-alkyl-3-ethynylaniline) or very reactive 4-haloquinazoline is used itis preferable to use t-butyl alcohol or a polar aprotic solvent such asDMF or N-methylpyrrolidin-2-one as the solvent.

Alternatively, a 4-substituted quinazoline 2 wherein X is hydroxyl oroxo (and the 2-nitrogen is hydrogenated) is reacted with carbontetrachloride and an optionally substituted triarylphosphine which isoptionally supported on an inert polymer (e.g. triphenylphosphine,polymer supported, Aldrich Cat. No. 36,645-5, which is a 2%divinylbenzene cross-linked polystyrene containing 3 mmol phosphorousper gram resin) in a solvent such as carbon tetrachloride, chloroform,dichloroethane, tetrahydrofuran, acetonitrile or other aprotic solventor mixtures thereof. The reaction mixture is maintained at a temperaturefrom about ambient to reflux, preferably from about 35° C. to reflux,for 2 to 24 hours. This mixture is reacted with the appropriate amine oramine hydrochloride 4 or 5 either directly or after removal of solvent,for example by vacuum evaporation, and addition of a suitablealternative solvent such as a (C₁-C₆) alcohol, DMF,N-methylpyrrolidin-2-one, pyridine or 1-4 dioxane. Then, the reactionmixture is maintained at a temperature from about ambient to the refluxtemperature of the solvent preferably from about 35° C. to about reflux,until substantially complete formation of product is acheived, typicallyfrom about 2 to about 24 hours. Preferably the reaction is performedunder an inert atmosphere such as dry nitrogen.

When compound 4, wherein Y is Br, I, or trifluoromethanesulfonyloxy, isused as starting material in the reaction with quinazoline 2, a compoundof formula 3 is formed wherein R¹, R², R³, and Y are as described above.Compound 3 is converted to compounds of formula 1 wherein R⁴ isR¹¹ethynyl, and R¹¹ is as defined above, by reaction with a suitablepalladium reagent such as tetrakis (triphenylphosphine)palladium orbis(triphenylphosphine) palladium dichloride in the presence of asuitable Lewis acid such as cuprous chloride and a suitable alkyne suchas trimethylsilylacetylene, propargyl alcohol or3-(N,N-dimethylamino)-propyne in a solvent such as diethylamine ortriethylamine. Compounds 3, wherein Y is NH₂, may be converted tocompounds 1 wherein R⁴ is azide by treatment of compound 3 with adiazotizing agent, such as an acid and a nitrite (e.g., acetic acid andNaNO₂) followed by treatment of the resulting product with an azide,such as NaN₃.

For the production of those compounds of Formula I wherein an R¹ is anamino or hydroxyamino group the reduction of the corresponding Formula Icompound wherein R¹ is nitro is employed.

The reduction may conveniently be carried out by any of the manyprocedures known for such transformations. The reduction may be carriedout, for example, by hydrogenation of the nitro compound in areaction-inert solvent in the presence of a suitable metal catalyst suchas palladium, platinum or nickel. A further suitable reducing agent is,for example, an activated metal such as activated iron (produced bywashing iron powder with a dilute solution of an acid such ashydrochloric acid). Thus, for example, the reduction may be carried outby heating a mixture of the nitro compound and the activated metal withconcentrated hydrochloric acid in a solvent such as a mixture of waterand an alcohol, for example, methanol or ethanol, to a temperature inthe range, for example, 50° to 150° C., conveniently at or near 70° C.Another suitable class of reducing agents are the alkali metaldithionites, such as sodium dithionite, which may be used in(C₁-C₄)alkanoic acids, (C₁-C₆)alkanols, water or mixtures thereof.

For the production of those compounds of Formula I wherein R² or R³incorporates a primary or secondary amino moiety (other than the aminogroup intended to react with the quinazoline), such free amino group ispreferably protected prior to the above described reaction followed bydeprotection, subsequent to the above described reaction with4-(substituted)quinazoline 2.

Several well known nitrogen protecting groups can be used. Such groupsinclude (C₁-C₆)alkoxycarbonyl, optionally substituted benzyloxycarbonyl,aryloxycarbonyl, trityl, vinyloxycarbonyl, O-nitrophenylsulfonyl,diphenylphosphinyl, p-toluenesulfonyl, and benzyl. The addition of thenitrogen protecting group may be carried out in a chlorinatedhydrocarbon solvent such as methylene chloride or 1,2-dichloroethane, oran ethereal solvent such as glyme, diglyme or THF, in the presence orabsence of a tertiary amine base such as triethylamine,diisopropylethylamine or pyridine, preferably triethylamine, at atemperature from about 0° C. to about 50° C., preferably about ambienttemperature. Alternatively, the protecting groups are . convenientlyattached using Schotten-Baumann conditions.

Subsequent to the above described coupling reaction, of compounds 2 and5, the protecting group may be removed by deprotecting methods known tothose skilled in the art such as treatment with trifluoroacetic acid inmethylene chloride for the tert-butoxycarbonyl protected products.

For a description of protecting groups and their use, see T. W. Greeneand P. G. M. Wuts, “Protective Groups in Organic Synthesis” Second Ed.,John Wiley & Sons, New York, 1991.

For the production of compounds of Formula I wherein R¹ or R² ishydroxy, cleavage of a Formula I compound wherein R¹ or R² is(C₁-C₄)alkoxy is preferred.

The cleavage reaction may conveniently be carried out by any of the manyprocedures known for such a transformation. Treatment of the protectedformula I derivative with molten pyridine hydrochloride (20-30 eq.) at150° to 175° C. may be employed for O-dealkylations. Alternatively, thecleavage reaction may be carried out, for example, by treatment of theprotected quinazoline derivative with an alkali metal(C₁-C₄)alkylsulphide, such as sodium ethanethiolate or by treatment withan alkali metal diarylphosphide such as lithium diphenylphosphide. Thecleavage reaction may also, conveniently, be carried out by treatment ofthe protected quinazoline derivative with a boron or aluminum trihalidesuch as boron tribromide. Such reactions are preferably carried out inthe presence of a reaction-inert solvent at a suitable temperature.

Compounds of formula I, wherein R¹ or R² is a (C₁-C₄) alkylsulphinyl or(C₁-C₄)alkylsulphonyl group are preferably prepared by oxidation of aformula I compound wherein R¹ or R² is a (C₁-C₄)alkylsulfanyl group.Suitable oxidizing agents are known in the art for the oxidation ofsulfanyl to sulphinyl and/or sulphonyl, e.g., hydrogen peroxide, aperacid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkalimetal peroxysulphate (such as potassium peroxymonosulphate), chromiumtrioxide or gaseous oxygen in the presence of platinum. The oxidation isgenerally carried out under as mild conditions as possible using thestoichiometric amount of oxidizing agent in order to reduce the risk ofover oxidation and damage to other functional groups. In general, thereaction is carried out in a suitable solvent such as methylenechloride, chloroform, acetone, tetrahydrofuran or tert-butyl methylether and at a temperature from about −25° to 50° C., preferably at ornear ambient temperature, i.e., in the range of 15° to 35° C. When acompound carrying a sulphinyl group is desired a milder oxidizing agentsshould be used such as sodium or potassium metaperiodate, convenientlyin a polar solvent such as acetic acid or ethanol. The compounds offormula I containing a (C₁-C₄)alkylsulphonyl group may be obtained byoxidation of the corresponding (C₁-C₄)alkylsulphinyl compound as well asof the corresponding (C₁C₄)alkylsulfanyl compound.

Compounds of formula I wherein R¹ is optionally substituted(C₂-C₄)alkanoylamino, ureido, 3-phenylureido, benzamido or sulfonamidocan be prepared by acylation or sulfonylation of a correspondingcompound wherein R¹ is amino. Suitable acylating agents are any agentsknown in the art for the acylation of amino to acylamino, for example,acyl halides, e.g., a (C₂-C₄)alkanoyl chloride or bromide or a benzoylchloride or bromide, alkanoic acid anhydrides or mixed anhydrides (e.g.,acetic anhydride or the mixed anhydride formed by the reaction of analkanoic acid and a (C₁-C₄)alkoxycarbonyl halide, for example (C₁-C₄)alkoxycarbonyl chloride, in the presence of a suitable base. For theproduction of those compounds of Formula I wherein R¹ is ureido or3-phenylureido, a suitable acylating agent is, for example, a cyanate,e.g., an alkali metal cyanate such as sodium cyanate, or an isocyanatesuch as phenyl isocyanate. N-sulfonylations may be carried out withsuitable sulfonyl halides or sulfonylanhydrides in the presence of atertiary amine base. In general the acylation or sulfonylation iscarried out in a reaction-inert solvent and at a temperature in therange of about −30° to 120° C., conveniently at or near ambienttemperature.

Compounds of Formula I wherein R¹ is (C₁-C₄)alkoxy or substituted(C₁-C₄)alkoxy or R¹ is (C₁-C₄)alkylamino or substituted mono-N- ordi-N,N-(C₁-C₄)alkylamino, are prepared by the alkylation, preferably inthe presence of a suitable base, of a corresponding compound wherein R¹is hydroxy or amino, respectively. Suitable alkylating agents includealkyl or substituted alkyl halides, for example, an optionallysubstituted (C₁-C₄)alkyl chloride, bromide or iodide, in the presence ofa suitable base in a reaction-inert solvent and at a temperature in therange of about 10° to 140° C., conveniently at or near ambienttemperature.

For the production of those compounds of Formula I wherein R¹ is anamino-, oxy- or cyano-substituted (C₁-C₄)alkyl substituent, acorresponding compound wherein R¹ is a (C₁-C₄)alkyl substituent bearinga group which is displacable by an amino-, alkoxy-, or cyano group isreacted with an appropriate amine, alcohol or cyanide, preferably in thepresence of a suitable base. The reaction is preferably carried out in areaction-inert solvent or diluent and at a temperature in the range ofabout 10° to 100° C., preferably at or near ambient temperature.

Compounds of Formula I, wherein R¹ is a carboxy substituent or asubstituent which includes a carboxy group are prepared by hydrolysis ofa corresponding compound wherein R¹ is a (C₁-C₄)alkoxycarbonylsubstituent or a substituent which includes a (C₁-C₄)alkoxycarbonylgroup. The hydrolysis may conveniently be performed, for example, underbasic conditions, e.g., in the presence of alkali metal hydroxide asillustrated in the accompanying Examples.

Compounds of Formula I wherein R¹ is amino, (C₁-C₄) alkylamino,di-[(C₁-C₄)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-(C₁-C₄) alkylpiperazin-1-yl or (C₁-C₄)alkysulfanyl,may be prepared by the reaction, in the presence of a suitable base, ofa corresponding compound wherein R¹ is an amine or thiol displaceablegroup with an appropriate amine or thiol. The reaction is preferablycarried out in a reaction-inert solvent or diluent and at a temperaturein the range of about 10° to 180° C., conveniently in the range 100° to150° C.

Compounds of Formula I wherein R¹ is 2-oxopyrrolidin-1-yl or2-oxopiperidin-1-yl are prepared by the cyclisation, in the presence ofa suitable base, of a corresponding compound wherein R¹ is ahalo-(C₂-C₄)alkanoylamino group. The reaction is preferably carried outin a reaction-inert solvent or diluent and at a temperature in the rangeof about 10° to 100° C., conveniently at or near ambient temperature.

For the production of compounds of Formula I in which R¹ is carbamoyl,substituted carbamoyl, alkanoyloxy or substituted alkanoyloxy, thecarbamoylation or acylation of a corresponding compound wherein R¹ ishydroxy is convenient.

Suitable acylating agents known in the art for acylation of hydroxyarylmoieties to alkanoyloxyaryl groups include, for example, (C₂-C₄)alkanoylhalides, (C₂-C₄)alkanoyl anhydrides and mixed anhydrides as describedabove, and suitable substituted derivatives thereof may be employed,typically in the presence of a suitable base. Alternatively,(C²-C₄)alkanoic acids or suitably substituted derivatives thereof may becoupled with a Formula I compound wherein R¹ is hydroxy with the aid ofa condensing agent such as a carbodiimide. For the production of thosecompounds of Formula I in which R¹ is carbamoyl or substitutedcarbamoyl, suitable carbamoylating agents are, for example, cyanates oralkyl or arylisocyanates, typically in the presence of a suitable base.Alternatively, suitable intermediates such as the chloroformate orcarbonylimidazolyl derivative of a compound of Formula I in which R¹ ishydroxy may be generated, for example, by treatment of said derivativewith phosgene (or a phosgene equivalent) or carbonyidiimidazole. Theresulting intermediate may then be reacted with an appropriate amine orsubstituted amine to produce the desired carbamoyl derivatives.

Compounds of formula I wherein R¹ is aminocarbonyl or a substitutedaminocarbonyl can be prepared by the aminolysis of a suitableintermediate in which R¹ is carboxy.

The activation and coupling of formula I compounds wherein R¹ is carboxymay be performed by a variety of methods known to those skilled in theart. Suitable methods include activation of the carboxyl as an acidhalide, azide, symmetric or mixed anhydride, or active ester ofappropriate reactivity for coupling with the desired amine. Examples ofsuch types of intermediates and their production and use in couplingswith amines may be found extensively in the literature; for example M.Bodansky and A. Bodansky, “The Practice of Peptide Synthesis”,Springer,-Verlag, New York, 1984. The resulting formula I compounds maybe isolated and purified by standard methods, such as solvent removaland recrystallization or chromatography.

The starting materials for the above described reaction schemes (e.g.,amines, quinazolines and amine protecting groups) are readily availableor can be easily synthesized by those skilled in the art usingconventional methods of organic synthesis. For example, the preparationof 2,3-dihydro-1,4-benzoxazine derivatives are described in R. C.Elderfield, W. H. Todd, S. Gerber, Ch. 12 in “Heterocyclic Compounds”,Vol. 6, R. C. Elderfield ed., John Wiley and Sons, Inc., N.Y., 1957.Substituted 2,3-dihydrobenzothiazinyl compounds are described by R. C.Elderfield and E. E. Harris in Ch. 13 of Volume 6 of the Elderfield“Heterocyclic Compounds” book.

Certain Formula I quinazolines can exist in solvated, as well asunsolvated forms, such as the hydrated forms. It is to be understoodthat the invention encompasses all such solvated, as well as unsolvatedforms, which possess activity against hyperproliferative diseases.

A suitable pharmaceutically-acceptable salt of a compound of formula Iis, for example, an acid-addition salt of a corresponding compound whichis sufficiently basic, e.g., an acid-addition salt with, for example, aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric,lactic or maleic acid. A suitable pharmaceutically-acceptablebase-addition salt of a compound of formula I which is acidic is analkali metal salt, for example, a lithium, sodium or potassium salt; analkaline earth metal salt, for example, a calcium or magnesium salt; anammonium salt; or a salt with an organic base which affords aphysiologically-acceptable cation for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine. All such salts are within the scope of thisinvention and they can be prepared by conventional methods. For example,they can be prepared simply by contacting the acidic and basic entities,usually in a stoichiometric ratio, in either an aqueous, non-aqueous orpartially aqueous medium, as appropriate. The salts are recovered byfiltration; by precipitation with a non-solvent, preferably an etheralor hydrocarbon solvent, followed by filtration and by evaporation of asolvent, or, in the case of aqueous solutions, by lyophilization.

Some of the compounds of Formula I have asymmetric carbon atoms. Suchdiasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known per se., for example, by chromatography and/or fractionalcrystallization. Enantiomers can be separated by converting theenantiomeric mixtures into a diastereomric mixture by reaction with anappropriate optically active compound (e.g., alcohol), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. All such isomers,including diastereomers mixtures and pure enantiomers are considered aspart of the invention.

The active compounds of this invention are potent inhibitors of the erbBfamily of oncogenic and protooncogenic protein tyrosine kinases such asepidermal growth factor receptor (EGFR), erbB2, HER3, or HER4 and thusare all adapted to therapeutic use as antiproliferative agents (e.g.,anticancer) in mammals, particularly humans. In particular, thecompounds of this invention are therapeutants or prophylactics for thetreatment of a variety of human tumors (renal, liver, kidney, bladder,breast, gastric, ovarian, colorectal, prostate, pancreatic, lung,vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, varioushead and neck tumors), and other hyperplastic conditions such as benignhyperplasia of the skin (e.g., psoriasis) or prostate (e.g., BPH). Itis, in addition, expected that a quinazoline of the present inventionmay possess activity against a range of leukemias and lymphoidmalignancies.

The active compounds may also be expected to be useful in the treatmentof additional disorders in which aberrant expression ligand/receptorinteractions, activation or signalling events related to various proteintyrosine kinases, whose activity is inhibited by the agents of FormulaI, are involved.

Such disorders may include those of neuronal, glial, astrocytal,hypothalamic, and other glandular, macrophagal, epithelial, stromal, andblastocoelic nature in which aberrant function, expression, activationor signalling of the erbB tyrosine kinases may be involved. In addition,compounds of Formula I may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases which are inhibited by compounds ofFormula I.

The in vitro activity of the active compounds in inhibiting the receptortyrosine kinase (and thus subsequent proliferative response, e.g.,cancer) may be determined by the procedure detailed below.

Activity of the active compunds, in vitro, can be determined by theamount of inhibition of the phosphorylation of an exogenous substrate(e.g., Lys₃-Gastrin or polyGluTyr (4:1) random copolymer (I. Posner et.al., J. Biol. Chem. 267 (29), 20638-47 (1992)) on tyrosine by epidermalgrowth factor receptor kinase by a test compound relative to a control.Affinity purified, soluble human EGF receptor (96 ng) is obtainedaccording to the procedure in G. N. Gill, W. Weber, Methods inEnzymology 146, 82-88 (1987) from A431 cells (American Type CultureCollection, Rockville, Md.) and preincubated in a microfuge tube withEGF (2 μg/ml) in phosphorylation buffer+vanadate (PBV: 50 mM HEPES, pH7.4; 125 mM NaCl; 24 mM MgCl₂; 100 μM sodium orthovanadate), in a totalvolume of 10 μl, for 20-30 minutes at room temperature. The testcompound, dissolved in dimethylsulfoxide (DMSO), is diluted in PBV, and10 μl is mixed with the EGF receptor /EGF mix, and incubated for 10-30minutes at 30° C. The phosphorylation reaction is initiated by additionof 20 μl ³³P-ATP/substrate mix (120 μM Lys₃-Gastrin (sequence in singleletter code for amino acids, KKKGPWLEEEEEAYGWLDF), 50 mM Hepes pH 7.4,40 μM ATP, 2 μCi γ-[³³P]-ATP) to the EGFr/EGF mix and incubated for 20minutes at room temperature. The reaction is stopped by addition of 10μl stop solution (0.5M EDTA, pH 8; 2mM ATP) and 6 μl 2N HCl. The tubesare centrifuged at 14,000 RPM, 4° C., for 10 minutes. 35 μl ofsupernatant from each tube is pipetted onto a 2.5 cm circle of WhatmanP81 paper, bulk washed four times in 5% acetic acid, 1 liter per wash,and then air dried. This results in the binding of substrate to thepaper with loss of free ATP on washing. The [³³P] incorporated ismeasured by liquid scintillation counting. Incorporation in the absenceof substrate (e.g., lys₃-gastrin) is subtracted from all values as abackground and percent inhibition is calculated relative to controlswithout test compound present.

Such assays, carried out with a range of doses of test compounds, allowthe determination of an approximate IC₅₀ value for the in vitroinhibition of EGFR kinase activity. Although the inhibitory propertiesof the compounds of Formula I vary with structural change as expected,the activity generally exhibited by these agents, determined in themanner described above, is in the range of IC₅₀=0.0001−30 μM.

Activity of the active compounds, in vivo, can be determined by theamount of inhibition of tumor growth by a test compound relative to acontrol. The tumor growth inhibitory effects of various compounds aremeasured according to the methods of Corbett T. H., et al. “TumorInduction Relationships in Development of Transplantable Cancers of theColon in Mice for Chemotherapy Assays, with a Note on CarcinogenStructure”, Cancer Res., 35, 2434-2439 (1975) and Corbett, T. H., etal., “A Mouse Colon-tumor Model for Experimental Therapy”, CancerChemother. Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications.Tumors are induced in the left flank by s.c. injection of 1×10⁶ logphase cultured tumor cells (human MDA-MB-468 breast or human HN5 headand neck carcinoma cells) suspended in 0.10 ml RPMI 1640. Aftersufficient time has elapsed for the tumors to become palpable (2-3 mm indiameter) the test animals (athymic mice) are treated with activecompound (formulated by dissolution in DMSO typically at a concentrationof 50 to 100 mg/mL followed by 1:9 dilution into saline or,alternatively, 1:9 dilution into 0.1% Pluronic® P105 in 0.9% saline) bythe intraperitoneal (ip) or oral (po) routes of administration twicedaily (i.e., every 12 hours) for 5 consecutive days. In order todetermine an anti-tumor effect, the tumor is measured in millimeterswith Vernier calipers across two diameters and the tumor size (mg) iscalculated using the formula: Tumor weight=(length×[width]²)/2,according to the methods of Geran, R. I., et al. “Protocols forScreening Chemical Agents and Natural Products Against Animal Tumors andOther Biological Systems”, Third Edition, Cancer Chemother. Rep., 3,1-104 (1972). Results are expressed as percent inhibition, according tothe formula: Inhibition(%)=(TuW_(control)−TuW_(test))/TUW_(control)×100%. The flank site oftumor implantation provides reproducible dose/response effects for avariety of chemotherapeutic agents, and the method of measurement (tumordiameter) is a reliable method for assessing tumor growth rates.

Administration of the active compounds can be effected by any methodwhich enables delivery of the compounds to the site of action (e.g.,cancer cells). These methods include oral routes, intraduodenal routes,parenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion), topical administration, etc.

The amount of active compound administered will, of course, be dependenton the subject being treated, on the severity of the affliction, on themanner of administration and on the judgement of the prescribingphysician. However an effective dosage is in the range of approximately0.001-100 mg/kg, preferably 1 to 35 mg/kg in single or divided doses.For an average 70 kg human, this would amount to 0.05 to 7 g/day,preferably 0.2 to 2.5 g/day.

The composition may, for example, be in a form suitable for oraladministration as a tablet, capsule, pill, powder, sustained releaseformulations, solution, suspension, for parenteral injection as asterile solution, suspension or emulsion, for topical administration asan ointment or cream or for rectal administration as a suppository. Thepharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Pharmaceutical compositions according to the invention may contain0.1%-95% of the compound, preferably 1%-70%. In any event, thecomposition or formulation to be administered will contain a quantity ofactive compound in an amount effective to alleviate or reduce the signsin the subject being treated, i.e., hyperproliferative diseases, overthe course of the treatment.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences., Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The hyperproliferative disease treatment described above may be appliedas a sole therapy or may involve, in addition to the active compound,one or more other antitumor substances. Such conjoint treatment may beachieved by way of the simultaneous, sequential, cyclic or separatedosing of the individual components of the treatment.

High pressure liquid chromatography (HPLC) used in the followingexamples and preparations was effected according to the following methodunless modified in specific examples. Perkin-Elmer Pecosphere® 3×3Ccartridge column (3mm×3cm, C18; available from Perkin Elmer Corp.,Norwalk, Conn. 06859) with a Brownlee (trademark) RP-8Newguard precolumn(7 micron, 3.2 mm×15 mm, available from Applied Biosystems Inc. SanJose, Calif. 95134) which was previously equilibrated in pH 4.50, 200 mMammonium acetate buffer. Samples were eluted using a linear gradient of0-100% acetonitrile/pH4.50, 200 mM NH₄ acetate over 10 minutes with aflow rate of 3.0 mL/min. Chromatograms were generated over the range240-400 nm using a diode array detector.

It should be understood that the invention is not limited to theparticular embodiments shown and described herein, but that variouschanges and modifications may be made without departing from the spiritand scope of the invention as defined by the claims.

EXAMPLE 1 (4-Azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amineHydrochloride

4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.12 mmol) and 4-azidoanilinehydrochloride (200 mg, 1.11 mmol) were refluxed in 10 mL of isopropylalcohol for 0.5 hour, cooled and filtered to afford solid title productwhich was washed with 10 mL of isopropyl alcohol and dried in vacuo, at70° C., 392 mg (98%); mp 200°-205° C. (dec).

EXAMPLE 2 (6,7-Dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amineHydrochloride

4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.12 mmol) and3-ethynyl-aniline (137 mg, 1.17 mmol) were refluxed in 10 mL ofisopropyl alcohol for 0.5 hour, cooled and filtered to afford solidtitle product which was washed with 10 mL of isopropyl alcohol and driedin vacuo, at 70° C., 338 mg (99%); mp 269°-270° C.

EXAMPLE 3(6,7-Dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine

A mixture of (3′-bromophenyl)-(6,7-dimethoxyquinazolin-4-yl)-aminehydrochloride (250 mg, 0.591 mmol),tetrakis(triphenylphosphine)palladium (100 mg), propargyl alcohol (600μL), 7 mL of dry, nitrogen purged diethylamine and cuprous iodide (10mg) was refluxed for 5 hours, cooled and filtered to afford solid titleproduct which was washed two times with 2 mL of 50%diethylamine:methanol; 136 mg. The solid was recrystallized frommethanol to give pure title product after drying, in vacuo,, at 70° C.,73 mg (37%); mp 267°-268° C.

EXAMPLE 4[(3-(2′-Aminomethyl-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amineHydrochloride

The title product of Example 3 (50 mg, 0.149 mmol), triphenylphosphine(60 mg, 0.225 mmol)), phthalimide (165 mg, 1.12 mmol) and diethylazodicarboxylate (36 μL, 0.228 mmol) were stirred at room temperature in3 mL of dry tetrahydrofuran for 16 hours. The reaction mixture wasconcentrated to a solid and flash chromatographed on silica gel elutedwith 15% acetone:methylene chloride to afford pure solid[3-(2′-{phthalimidomethyl}-ethynyl)phenyl]-(6,7-dimethoxyquinazoline-4-yl)aminewhich was converted to its hydrochloride salt by addition of 1 mL ofanhydrous 1M HCl in methanol followed by 3 mL of isopropyl alcohol. Thesalt was collected by filtration, dried and used immediately in the nextstep; 15 mg. This 15 mg, 0.0323 mmol was treated with 0.5 ml ofhydrazine hydrate and 1 mL of methanol for 0.5 hours. The reactionmixture was evaporated, in vacuo, and the product isolated by flashchromatography eluted with 10% methanol in methylene chloride. Puretitle product was isolated after conversion to its hydrochloride saltwith 1 mL of 1M HCl in methanol, precipitation with isopropyl alcoholand diethyl ether and drying, in vacuo,; 5.6 mg (47%) mp 275° C. dec.

EXAMPLE 5 (3-Ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine Hydrochloride

4-Chloro-6-nitroquinazoline (1.06 g,5.00 mmol) and 3-ethynylaniline(1.00 g,5.30 mmol) were refluxed in 10 mL of isopropyl alcohol for 3hours, cooled and, after 16 hours at room temperature, filtered toafford solid title product which was washed with 10 mL of isopropylalcohol and dried in vacuo, at 70° C., 1.27 g (78%); mp 255°-256° C.

EXAMPLE 6 (6,7-Dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine

The title product was prepared in the following three step sequencewithout purification of the intermediates.4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.113 mmol) and 4-iodoaniline(268 mg, 1.224 mmol) were refluxed in 10 mL of isopropyl alcohol for 3hours, cooled to room temperature and filtered to afford solid(4-iodophenyl)-(6,7-dimethoxyquinazoline-4-yl)amine hydrochloride whichwas washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C.,396 mg (76%). A mixture consisting of(4′-iodophenyl)-(6,7-dimethoxyquinazoline-4-yl)amine hydrochloride (250mg, 0.564 mmol), tetrakis (triphenylphosphine)palladium (50 mg),trimethylsilylacetylene (160 μL, 1.13 mmol), 4 mL of dry, nitrogenpurged diethylamine and cuprous iodide (10 mg) was refluxed for 2 hours,cooled and concentrated in vacuo, to afford a residue which waspartitioned between chloroform and 1N HCL. Solid[4-(2′-{trimethylsilyl}-ethynyl)phenyl]-(6,7-dimethoxyquinazoline-4-yl)amine formed at the interface ofthe two liquid phases and was filtered and dried in vacuo; 170 mg (80%).

[4-(2′-{Trimethylsilyl}ethynyl)phenyl]-(6,7-dimethoxyquinazoline-4-yl)amine(100 mg, 0.265 mmol) and anhydrous potassium carbonate (125 mg, 0.906mmol) were stirred in 3 mL of methanol and 1 mL of water at roomtemperature for 2.5 hours. The reaction mixture was concentrated invacuo, and partitioned between 20 mL of chloroform and 20 mL of 1Nhydrochloric acid. The organic layer was dried with magnesium sulfate,filtered and vacuum evaporated to give the title product which wastriturated with diethyl ether and dried in vacuo at 70° C.; 81 mg (90%)mp 239° C. dec.

EXAMPLE 7(6,7-Dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine

The title product was prepared in the following three step sequence without purification of the intermediates. A mixture consisting of3-bromo-2-methylaniline (1.00 g, 5.37 mmol),tetrakis(triphenylphosphine)palladium (200 mg), trimethylsilylacetylene(1.053 g, 10.75 mmol), 10 mL of dry, nitrogen purged diethylamine andcuprous iodide 910 mg) was refluxed for 16 hours, cooled andconcentrated, in vacuo, to afford a residue which was partitionedbetween chloroform and 1N HCL. The organic layer was washed with brine,dried with magnesium sulfate and vacuum evaporated to yield a residue,3-[2′-(trimethylsilyl)ethynyl]-2-methylaniline which was purified byflash chromatography on silica gel eluted with 1:1 hexanes:methylenechloride; 200 mg (18%).

4-Chloro-6,7-dimethoxyquinazoline (104 mg, 0.466 mmol) and3-[2′-(trimethylsilyl)ethinyl]-2-methylaniline (100 mg, 0.491 mmol) wererefluxed in 3 mL of isopropyl alcohol for 16 hour, cooled to roomtemperature and filtered to afford a residue of solid{3-[2′-(trimethylsilyl)ethynyl]-2′-methylphenyl|}-(6,7dimethoxyquinazoline-4-yl)amine hydrochloride which was washed with 10 mL of isopropylalcohol and triturated for 16 hours with diethyl ether. Thin layerchromatography on silica gel eluted with 9:1 chloroform:methanolindicated that the residue was impure product. The residue was purifiedby flash chromatography on silica gel eluted with 9:1 methylenechloride:methanol to afford after concentration and drying, in vacuo,pure product, 64 mg (33%). The product was dissolved in 3 mL of methanoland treated with 64 mg of anhydrous potassium carbonate at roomtemperature for 3 hours. The reaction mixture was concentrated in vacuoand partitioned between 1N HCl and chloroform. Solid title productformed at the interface of the two liquid phases and was filtered anddried, in vacuo; 40 mg (84%) mp 225° C. dec.

EXAMPLE 8 (6-Amino-quinazolin-4-yl)-(3-ethynylphenyl)-amine

(3-Ethynyl-phenyl)-(6-nitro-quinazolin-4-yl)-amine hydrochloride (500mg, 1.50 mmol) was dissolved in 10 mL of formic acid and treatedportion-wise with sodium dithionite (1.10 g, 6.28 mmol) at roomtemperature. After 2 hours the mixture was quenched with 120 mL of waterand filtered. The filtrate was evaporated in vacuo to a residue whichwas dissolved in 100 mL of 1:1 methanol:chloroform, filtered andevaporated in vacuo to a second residue. This was triturated with 200 mLof 5% sodium bicarbonate for 30 minutes, filtered, washed with water anddried in vacuo for 16 hours. Flash chromatography on silica gel elutedwith ethyl acetate afforded pure(6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; 140 mg (34%); mp 165°C. dec.

EXAMPLE 9(3-Ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl}-amine

The title product of Example 8 (100 mg, 0.384 mmol), pyridine (140 μL,1.68 mmol) and methanesulfonyl chloride (99 μL, 1.26 mmol) were refluxedin 10 mL of 1,2-dichloroethane for 7 hours. The reaction mixture wascooled and evaporated in a vacuo to a residue which was triturated in 10mL of 1N HCl, filtered and dried in vacuo to yield(3-ethynylphenyl)-(6-methanesulfonylaminoquinazoline-4-yl)amine; 102 mg(78%) mp 248° C. dec.

EXAMPLE 10 (3-Ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amineHydrochloride

4-Chloro-6,7-methylenedioxyquinazoline (200 mg, 1.04 mmol) and3-ethynylaniline (127 mg, 1.09 mmol) were refluxed in 5 mL of isopropylalcohol for 16 hour, cooled and filtered to afford solid title productwhich was washed with 10 mL of isopropyl alcohol and dried in vacuo at70° C., 266 mg (79%); mp >350° C.

EXAMPLE 11((6,7-Dimethoxyquinazolin-4-yl)-3-ethynyl-6-methylphenyl)-amineHydrochloride

The title product was prepared in the following three step sequencewithout purification of the intermediates. A mixture consisting of4-bromo-2-nitrotoluene (1.50 g, 6.94 mmol)tetrakis(triphenylphosphine)palladium (750 mg), trimethylsilylacetylene(3.00 mL, 21.21 mmol) and cuprous iodide (20 mg) in 20 mL of nitrogenpurged, dry diethylamine was refluxed for 2 hours, cooled andconcentrated, in vacuo, to afford a residue which was partitionedbetween 100 mL of ethyl acetate and 100 mL of 1N HCl. The organic layerwas washed two times with 50 mL of 1N HCl followed by brine, dried withmagnesium sulfate and vacuum evaporated to a residue. The residue wasdissolved in 10 mL of ethyl acetate and diluted with 200 mL of petroleumether. The solids were filtered off and the oil, obtained upon vacuumevaporation of the filtrate, solidified to give4-[2′-(trimethylsilyl)ethinyl]-2-nitrotoluene. This product was reducedto the amino product by treatment with iron powder (1.76 g, 98.5 mmol)in 30 mL of methanol and 5 mL of concentrated hydrochloric acid at 80°C. for 2 hours. The cooled reaction mixture was filtered through Celite®and the filtrate was evaporated in vacuum. The residue was partitionedbetween ethyl acetate and 5% aqueous sodium bicarbonate. The organiclayer was washed with brine, dried with magnesium sulfate, filtered andvacuum evaporated to yield an oil,5-[2′-(trimethylsilyl)ethynyl)-2-methylaniline which solidified uponstanding: 1.37 g.

The above product (185 mg, 0.909 mmol) and4-chloro-6,7-dimethoxyquinazoline (200 mg, 0.890 mmol) were refluxed intert-butyl alcohol for 16 hours. After cooling the reaction mixture wasfiltered to yield pure[2-methyl-5-(2′-{trimethylsilyl}-ethynyl)-phenyl]-(6,7-dimethoxyquinazoline-4-yl-aminehydrochloride after washing with ether and drying in vacuum; 326 mg(85%). The trimethylsilyl group was removed by dissolving the aboveproduct in 5 mL of methanol and 1 mL of water and treatment withpotassium carbonate (320 mg). After stirring for 1 hour the mixture wasfiltered and concentrated in vacuo. The residue thus obtained waspartitioned between 100 mL of methylene chloride and 100 mL of 1N HCl.The aqueous layer was extracted with an additional 100 mL of methylenechloride. The pooled organic layers were dried with magnesium sulfate,filtered and vacuum evaporated to a residue which was dissolved inanhydrous 1N HCl in methanol, concentrated and precipitated with ether.The solid title product was collected by filtration and washed withdiethyl ether then dried in vacuo at 70° C.; 236 mg (88%) mp 266°-267°C.

EXAMPLE 12 (3-Ethynylphenyl)-(7-nitroquinazolin-4-yl)-amineHydrochloride

4-Chloro-7-nitroquinazoline (7.97 g, 38.0 mmol) and 3-ethynylaniline(4.54 g, 38.8 mmol) were refluxed in 125 mL of tert-butyl alcohol for 3hours, cooled to room temperature and filtered to afford the titleproduct as a solid which was washed with 10 mL of isopropyl alcohol anddried in vacuo at 70° C., 9.95 g (80%); mp 209°-210° C. dec.

EXAMPLE 13(3-Ethynylphenyl)-[6-(4′-toluenesulfonylamino)-quinazolin-4-yl]-amineHydrochloride

The title product of example 8 (0.201 mg, 0.774 mmol) and4-toluenesulfonyl chloride (0.441 mg, 2.31 mmol) were refluxed in 3 mLof 1,2-dichloroethane and 0.5 mL of pyridine for 5 minutes. The reactionmixture was cooled to room temperature, diluted with 75 mL of ethylacetate and washed two times with 75 mL of water once with 75 mL of 3%sodium bicarbonate and once with 75 mL of brine. The organic layer wasdried with magnesium sulfate, filtered and vacuum evaporated to aresidue which was purified by chromatography using a Chromatotron(trademark) eluted with ethyl acetate, to afford solid title product;86.7 mg (27%) mp 220°-222° C.

EXAMPLE 14(3-Ethynylphenyl)-{6-[2′-phthalimido-ethan-1′-ylsulfonylamino]quinazolin-4-yl}-amineHydrochloride

The title product of example 8 (0.20 mg, 0.768 mmol) and2-phthalimido-1-ethanesulfonyl chloride (0.615 mg, 2.25 mmol) wererefluxed in 2 mL of 1,2-dichloroethane and 0.5 mL of pyridine for 16hours, cooled to room temperature, diluted with 100 mL of chloroform andwashed with 50 mL of 3% sodium bicarbonate and 50 mL of brine. Theorganic layer was dried with magnesium sulfate, filtered and vacuumevaporated to a residue which was dissolved in minimal methylenechloride and precipitated with petroleum ether, 188 mg. The precipitatewas purified by chromatography using Chromatotron@ eluted with ethylacetate, to afford the title product as a solid; 53.4 mg (14%) mp197°-200° C.

EXAMPLE 15 (3-Ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amineHydrochloride

The title product of example 8, (0.302 mg, 1.16 mmol) and3,5-dimethylpyrazole-1-carboxamidine (0.328 mg, 2.36 mmol) were refluxedin 10 mL of 1,2-dichloroethane and 0.97 mL of acetic acid for 24 hours,cooled to room temperature and filtered to yield the crude acetate ofthe title product. The product was dissolved in 35 mL of methanol andtreated with 15 mL of anhydrous 1N HCl in methanol for 15 minutes andthen precipitated with 75 mL of diethyl ether. Solid title product wascollected by filtration and dried in vacuo at 70° C.; 91.2 mg (23%)mp>400° C.

EXAMPLE 16 (7-Aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine

The title product of example 12 (1.039 g, 3.18 mmol) was dissolved in 50mL of tetrahydrofuran, 10 mL of methanol and 5 mL of chloroform at 50°C. Sodium dihydrogen phosphite (NaH₂PO₂, 3.822 g, 36 mmol) and 10%palladium on carbon (0.19 g) were added followed by dropwise addition of10 mL of water. When 3 mL of water had been added the mixture becamenoticeably more homogeneous. After 1 hour the mixture was filteredthrough Celite. The Celite was washed thoroughly with methanol andchloroform. The combined organic solutions were vacuum evaporated to aresidue which was triturated with water, 3% aqueous sodium bicarbonateand filtered. The solid title product was washed with water then diethylether and dried in vacuo, 1.054 gm (127%, wet). A portion of the aboveproduct was recrystallized from a minimum amount of hot ethanol andwater to give, after removal of a small first crop of impure material,pure title product, (43%), mp 180° C. (dec).

EXAMPLE 17 (3-Ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amineHydrochloride

4-Chloro-7-methoxyquinazoline (274 mg, 3.72 mmol) and 3-ethynylaniline(436 mg, 3.72 mmol) were refluxed in 15 mL of tert-butyl alcohol for 3hours, cooled and filtered to afford solid title product which waswashed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 977mg (84%); mp 229°-231° C.

EXAMPLE 18 (6-Carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amineHydrochloride

4-Chloro-6-carbomethoxyquinazoline (100 mg, 0.450 mmol) and3-ethynylaniline hydrochloride (53.4 mg, 0.456 mmol) were refluxed in 2mL of tert-butyl alcohol for 2 hours, cooled, diluted with 2 mL ofisopropyl alcohol and filtered to afford solid title product which waswashed with 10 mL of diethyl ether and dried, in vacuo, at 70° C., 122mg (80%); mp 232°-233° C. (dec).

EXAMPLE 19 (7-Carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amineHydrochloride

4-Chloro-7-carbomethoxyquinazoline (202 mg, 0.907 mmol) and3-ethynylaniline (110 mg, 0.939 mmol) were refluxed in 4 mL oftert-butyl alcohol for 2 hours, cooled, diluted with 4 mL of isopropylalcohol and filtered to afford solid title product which was washed with10 mL of diethyl ether and dried, in vacuo, at 70° C., 248 mg (80%); mp219.5°-221° C.

EXAMPLE 20[6-,7-Bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amineHydrochloride

3-Ethynylaniline (37 mg, 0.32 mmol.), and4-chloro-6,7-bis-(2-methoxy-ethoxy)quinazoline (90 mg, 0.29 mmol) wereadded to isopropanol (1.5 mL) containing pyridine (25 μL, 0.32 mmol) andthe mixture was refluxed 4 hours under an atomospher of dry nitrogen.The solvent was removed, in vacuo, and the residue partitioned between10% methanol in CHCl₃ and saturated aqueous NaHCO₃. The organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas flash chromatographed on silica using 30% acetone in hexanes toafford 81 mg of the free base of the title product as a pale yellowsolid. The free-base was dissolved in a minimum volume of CHCl₃, dilutedwith several volumes of ether, and titrated with 1M HCl in ether toprecipitate the title product as its hydrochloride salt; 90 mg; 71%; mp228°-230° C.

EXAMPLE 21 (3-Azidophenyl)-(6,7-dimethoxyquinazolin-4-yl) amine

4-Chloro-6,7-dimethoxyquinazoline (5.01 g, 22.3 mmol) was added inportions, over 1.5 hours, to m-phenylenediamine (2.66 g, 24.6 mmol) inrefluxing isopropanol (100 mL) under an atmosphere of dry nitrogen.After the addition was complete the mixture was heated at reflux for 4hours. The mixture was cooled to 20° C., and the precipitate wasfiltered, washed with chilled isopropanol and dried in vacuo to afford6.97 g (93%) of (3-aminophenyl)-(6,7-dimethoxyquinazolin-4-yl)aminehydrochloride (LC-MS: 297 (MH⁺). To a solution of the above product (50mg, 0.169 mmol) in 80% acetic acid/H₂O (2 mL), at 0° C., was added asolution of NaNO₂ (18.4 mg, 0.186 mmol) in H₂O (100 μL). After stirring10 minutes at 0° C. a solution of NaN₃ (12 mg, 0.185 mmol) in H₂O (100μL) was added. The mixture was allowed to warm to 20° C. and stirred for1.5 hours. The reaction mixture was lyophilized and the residuepartitioned between ethyl acetate and saturated aqueous NaHCO₃. Theorganic phase was wahsed further with brine, dried over Na₂SO₄,filtered, and concentrated, in vacuo. Recrystallization fromCHCl₃/hexanes afforded 36 mg of the title product as a white solid; mp110°-113° C.

EXAMPLE 22 (3-Azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine

4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) and5-amino-3-chloroaniline (253 mg, 1.78 mmol) were combined in isopropanol(3 mL) and heated to reflux for 16 hours under an atmosphere of drynitrogen. After cooling to 20° C. the mixture was diluted with methanol(5 mL) and the resulting precipitate was filtered and dried, in vacuo,to afford 252 mg (77%) of(3-amino-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)aminehydrochloride (mp. 298°-301° C.; LC-MS: 331 (MH+)). A portion of thisproduct (175 mg, 0.476 mmol) was dissolved in 80% acetic acid/H₂O (12mL), cooled to 0° C., and a solution of NaNO₂ (36 mg, 0.516 mmol) in H₂O(300 μL) was added. The solution was stirred for 10 minutes at 0° C. andNaN₃ (33 mg, 0.50 mmol) in H₂O (300 μL) was added. The reaction mixturewas allowed to warm to 20° C. and stirred 16 hours. The resultingprecipitate was filtered and dissolved in 10% methanol in CHCl₃ and thesolution was washed with saturated aqueous NaHCO₃, and brine, dried overNa₂SO₄, filtered and concentrated in vacuo to yield 59 mg (35%) of thetitle product as a yellow solid; mp 205°-206° C.

EXAMPLE 23 (3-Ethynylphenyl)-(6-methanesulfonyl-quinazolin-4-yl-amineHydrochloride

6-Methanesulfonyl-quinazolin-4-one (200 mg, 0.89 mmol), triphenylphosphine (566 mg, 2.15 mmol) and carbon tetrachloride (815 μL, 8.92mmol) were refluxed in 3 mL of chloroform for 3.5 hours. The solvent wasvacuum evaporated to afford a residue. This was dissolved in 5 mL ofisopropyl alcohol and 3-ethynylaniline (156 mg, 1.33 mmol) and heated atreflux for 16 hours. The cooled reaction mixture was filtered, washedwith a minimum of cold isopropyl alcohol and dried in vacuo at 70° C.for 16 hours to afford pure title product; 63 mg (20%) mp 281°-282° C.

EXAMPLE 24 (6-Ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amineHydrochloride

6-Ethanesulfanyl-quinazolin-4-one (100 mg, 0.48 mmol), triphenylphosphine (305 mg, 1.16 mmol) and 3 mL of carbon tetrachloride wererefluxed for 16 hours. The solvent was vacuum evaporated to afford aresidue. This was dissolved in 5 mL of isopropyl alcohol and3-ethynylaniline (68 mg, 0.58 mmol) and heated at reflux for 1 hour. Thecooled reaction mixture was filtered, washed with a minimum of coldisopropyl alcohol and dried in vacuo at 70° C. for 16 hours to affordpure title product; 70 mg (42%) mp 239°-40° C.

EXAMPLE 25(6,7-Dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amineHydrochloride

4-Chloro-6,7-dimethoxyquinazoline (500 mg, 2.23 mmol) and3-(2′-trimethylsilylethynyl)-4-fluoroaniline (507 mg, 2.44 mmol) wererefluxed in 5 mL of tert-butyl alcohol for 16 hours, cooled and filteredto afford solid(6,7-dimethoxy-quinazolin-4-yl)-(3′-ethynyl-phenyl)-amine hydrochloridewhich was washed with 10 mL of isopropyl alcohol and dried in vacuo at70° C., 832 mg (83%). This was reacted in 10 mL of methanol and 1 dropof water containing 250 mg of potassium carbonate for 3 hours. Themixture was filtered and the filtrate vacuum evaoprated. This residuewas triturated for 1 hour with 1N hydrochloric acid, filtered and washedwith a minimum amount of water then methanol and dried in vacuo; 506 mg(63%) mp 229° C. dec.

3-(2′-Trimethylsilyl-ethynyl)-4-fluoroaniline, used above, was preparedfrom 3-bromo-4-fluoroaniline (7.0 gm, 36.8 mmol)tetrakis(triphenylphosphine)palladium (1.4 gm), trimethylsilyl-acetylene(7.2 gm, 74 mmol) and cuprous iodide (40 mg) in 140 mL of nitrogenpurged dry diethylamine at reflux for 16 hours. The cooled reactionmixture was filtered through Celite and the Celite washed with ether.The combined filtrates were vacuum evaporated to a residue which waspurified by flash chromatography on silica gel eluted with 35% hexanesin methylene chloride. Fractions containing the pure3-(2′-trimethylsilyl-ethynyl)-4-fluoroaniline were vacuum evaporated toa residue and used without further purification.

EXAMPLE 26 (6,7-Dimethoxy-quinazolin-4-yl)-(3-propyn-1-yl)phenyl)-amineHydrochloride

4-Chloro-6,7-dimethoxyquinazoline (585 mg, 2.60 mmol) and3-(propyn-1-yl)aniline (361 mg, 2.74 mmol) were refluxed in 5 mL oftert-butyl alcohol for 16 hours, cooled and filtered to afford solid(6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1-yl)phenyl)]-aminehydrochloride which was washed with 5 mL of isopropyl alcohol and 25 mLof ether then dried in vacuo at 70° C., 869 mg (94%); mp 260°-261° C.

3-(Propyn-1-yl)aniline, used above, was prepared from3-bromo-nitrobenzene in four steps. 3-Bromo-nitrobenzene (5.0 gm, 24.7mmol), tetrakis(triphenylphosphine)palladium (1.0 gm),trimethylsilyl-acetylene (3.6 gm, 37 mmol) and cuprous iodide (20 mg) in20 mL of nitrogen purged, dry diethylamine at reflux for 16 hours. Thecooled reaction mixture was vacuum evaporated, diluted with 50 mL ofmethylene chloride and 50 mL of 1N hydrochloric acid and filtered. Theorganic layer was collected and dried with magnesium sulfate filteredand vacuum evaporated to a residue. The3-trimethylsilylethynylnitrobenzene was purified by flash chromatographyon silica gel eluted with 2:1 hexanes:methylene chloride. Fractionscontaining the pure material were vacuum evaporated to afford pure3-trimethylsilylethynyl nitrobenzene (4.6 gm). 4.0 gm of this weredissolved in 30 mL of methanol and 1 drop of water containing 1.16 gm ofpotassium carbonate. After one hour the mixture was vacuum evaporatedand diluted with 100 mL of methylene chloride. The organic layer waswashed with 100 mL of 1N hydrochloric acid, dried with magnesiumsulfate, filtered and vacuum evaporated to a residue (2.96 gm). 790 mgof this was dissolved in 10 mL of benzene and treated with finelypulverized 87% potassium hydroxide (377 mg, 5.91 mmol), methyl iodide (2mL) and 10 mg of 18-Crown-6 (Aldrich) at reflux for 16 hours. Anadditional 0.5 mL of methyl iodide were added and the reflux continuedfor an additional 2 hours. The cooled reaction mixture was vacuumevaporated to a residue which was diluted with 100 mL of methylenechloride and washed with 100 mL of 1N hydrochloric acid, dried withmagnesium sulfate, filtered and vacuum evaporated to an oil. This waspurified by flash chromatography on silica gel eluted with 1:1hexanes:methylene chloride. Fractions containing pure3-(propyn-1-yl)-nitrobenzene were vacuum evaporated to an oil which wasused without further purification; 530 mg (61%).3-(Propyn-1-yl)-nitrobenzene (530 mg, 3.3 mmol), iron powder (400 mg,7.27 mmol), 3 mL of concentrated hydrochloric acid and 10 mL of methanolwere refluxed for 1 hour. The reaction mixture was filtered and vacuumevaporated to a solid which was partitioned between 100 mL of methylenechloride and 100 mL of 1N sodium hydroxide. The two phases were filteredand then the organic phase was separated, dried with magnesium sulfate,filtered and vacuum evaporated to an oil which was used directly in thepreparation of the title product; 321 mg (78%).

EXAMPLE 27[6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amineHydrochloride

4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (140 mg, 0.446 mmol) and3-ethynyl-4-fluoroaniline (66 mg, 0.452 mmol) were reacted in refluxingisopropanol (3 mL) under an atmosphere of N₂ for 16 hours. The solventwas removed in vacuo and the residue was partitioned between CHCl₃ andsaturated aqueous NaHCO₃. The organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas chromatographed on silica using 40% acetone/CH₂Cl₂ to provide 116 mgof the pure title product as its free base. This oil was dissolved in aminimum volume of CHCl₃, diluted with several volumes of ether andtitrated with 1M HCl in ether to precipitate the title product as awhite solid (99 mg; 50%; M.P. 170°-190° C. (dec); LC-MS: 412 (MH⁺);anal. RP18-HPLC RT: 4.33 min.).

EXAMPLE 28[6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amineHydrochloride

4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (153 mg, 0.49 mmol),pyridine (40 μL) and 3-ethynyl-6-methylaniline (71 mg, 0.54 mmol) werereacted in DMF (3 mL) at 110° C. under an atmosphere of N₂ for 36 hours.The solvent was removed in vacuo and the residue was partitioned betweenCHCl₃ and saturated aqueous NaHCO₃. The organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was chromatographed on silica using 40% acetone/CH₂Cl₂ toprovide 40 mg (19%) of pure product as its free base. This oil wasdissolved in a minimum volume of CHCl₃, diluted with several volumes ofether, and triturated with 1M HCl in ether to precipitate the titleproduct as a white solid (M.P. 170°-185° C. (dec); LC-MS: 408 (MH⁺);anal. RP18-HPLC RT: 3.93 min.).

EXAMPLE 29[6,7-Bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amineHydrochloride

4-Chloro-6,7-bis-(2-chloro-ethoxy)-quinazoline (600 mg, 1.87 mmol) and3-ethynyl-aniline (219 mg, 1.87 mmol) were reacted in refluxingisopropanol (15 mL) under an atmosphere of N₂ for 2.5 hours. The mixturewas cooled to 20° C. and the precipitated product was filtered, washedWith isopropanol and ether and dried in vacuo. (707 mg; 86%; M.P.230°-240° C. (dec); LC-MS: 402 (MH⁺); anal. RP18-HPLC RT: 5.35 min.).

EXAMPLE 30[6-(2-Chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amineHydrochloride

The title product was prepared from4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxyethoxy)-quinazoline (399 mg,1.26 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described forExample 29. (515 mg; 94%; M.P. 215°-225° C. (dec); LC-MS: 398 (MH⁺);anal. RP18-HPLC RT: 4.85 min.).

EXAMPLE 316,7-Bis(2-acetoxy-ethoxy)-4-(3-ethynyl-phenylamino)-quinazoline

The title product of Example 29 (200 mg, 0.456 mmol) was treated withcesuim acetate (1.75 g, 9.12 mmol) in DMF (3 mL) at 120° C. under anatmosphere of N₂ for 16 hours. The reaction mixture was partitionedbetween brine and CHCl₃, and the organic extract was washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford an oil(277 mg) which was recrystallized from CH₂Cl₂/hexane. (184 mg; 90%; M.P.137°-138° C.; LC-MS: 450 (MH⁺); anal. RP18-HPLC RT: 4.64 min.).

EXAMPLE 322-[4-(3-Ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanolHydrochloride

6,7-Bis-(2-acetoxy-ethoxy)-4-(3-ethynyl-phenyl-amino)-quinazoline (199mg, 0.443 mmol) in methanol (3 mL) was treated with 7M aqueous KOH (0.25mL). The mixture was stirred at 20° C. for 2 hours before removing thesolvent in vacuo. The solid residue was washed with water to removesalts, and dried azeotropically by dissolution two times in acetonitrileand concentration in vacuo to afford 116 mg of title product as its freebase. This material was converted to its HCl salt according to themethod used in Example 28 (115 mg; 65%; M.P.215°-218° C. (dec); LC-MS:366 (MH⁺); anal. RP18-HPLC RT: 3.08 min.).

EXAMPLE 336-(2-Acetoxy-ethoxy)-4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazoline

The title product of Example 30 (160 mg, 0.368 mmol); was treated withcesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under anatmosphere of N₂ for 16 hours. The reaction mixture was partitionedbetween brine and CHCl₃, and the organic extract was washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford aresidue (285 mg) which was recrystallized from ethylacetate/hexane. (134mg; M.P. 84°-87° C.; LC-MS: 422 (MH⁺); anal. RP18-HPLC RT: 4.38 min.).

EXAMPLE 34[7-(2-Chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amineHydrochloride

This product was prepared from4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline (600 mg,1.89 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described forExample 29. (737 mg; 90%; M.P. 225°-235° C. (dec); LC-MS: 398 (MH⁺);anal. RP18-HPLC RT: 4.89 min.).

EXAMPLE 357-(2-Acetoxy-ethoxy)-4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazoline

The title product of Example 34 (160 mg, 0.368 mmol); was treated withcesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under anatmosphere of N₂ for 16 hours. The reaction mixture was partitionedbetween brine and CHCl₃, and the organic extract was washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford aresidue (288 mg) which was recrystallized from ethyl acetate/hexanes.(134 mg; M.P.134°-135° C.; LC-MS: 422 (MH⁺); anal. RP18-HPLC RT: 4.43min.).

EXAMPLE 362-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yl-oxy]-ethanolHydrochloride

The title product of Example 35 (149 mg, 0.354 mmol) in methanol (3 mL)was treated with 5M aqueous KOH (0.25 mL). The mixture was stirred at20° C. for 30 minutes before removing the solvent in vacuo. The solidresidue was washed with water to remove salts, and dried azeotropicallyby dissolution two times in acetonitrile and concentration in vacuo toafford 100 mg of title product as its free base. This material wasconverted to its HCl salt according to the method used in Example 28 (87mg; 59%; M.P. 230°-235° C. (dec); LC-MS: 380 (MH⁺); anal. RP18-HPLC RT:3.42 min.).

EXAMPLE 37(3-Ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amineDihydrochloride

The title product of Example 34 (110 mg, 0.253 mmol) in DMF (2 mL) wastreated with N-methyl-piperazine (281 μL, 2.53 mmol) at 110° C. for 16hours. The reaction mixture was partitioned between CHCl₃ and saturatedaqueous NaHCO₃. The organic extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waschromatographed on silica using 15% methanol/CH₂Cl₂ to provide 56 mg ofpure product as its free base. This white solid was dissolved in aminimum volume of CHCl₃, and titrated with 2 equivalents of 1M HCl inether to precipitate the title product as a white solid (65 mg; 48%;M.P. 130°-142° C. (dec); LC-MS: 462 (MH⁺); anal. RP18-HPLC RT: 3.69min.).

EXAMPLE 38(3-Ethynyl-phenyl)-[7-(2-imidazol-1-yl-ethoxy)-6-(2-methoxy-ethoxy)quinazolin-4-yl]-amineDihydrochloride

The title product from Example 34 (110 mg, 0.253 mmol) in DMF (2 mL) wastreated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. Thereaction mixture was partitioned between CHCl₃ and saturated aqueousNaHCO₃. The organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product (119 mg) waschromatographed on silica using 10% methanol/CH₂Cl₂ to provide 85 mg ofpure title product as its free base. This white solid was dissolved in aminimum volume of CHCl₃, and titrated with 2 equivalents of 1M HCl inether to precipitate the title product as a white solid (95 mg; 75%;M.P. 220°-227° C. (dec); LC-MS: 430 (MH⁺); anal. RP18-HPLC RT: 3.75min.).

EXAMPLE 39(3-Ethynyl-phenyl)-[6-(2-imidazol-1-yl-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-amineDihydrochloride

The title product of Example 30 (110 mg, 0.253 mmol) in DMF (2 mL) wastreated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. Thereaction mixture was partitioned between CHCl₃ and saturated aqueousNaHCO₃. The organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product (125 mg) waschromatographed on silica using 10% methanol/CH₂Cl₂ to provide 86 mg ofpure title product as its free base. This white solid was dissolved in aminimum volume of CHCl₃, and titrated with 2 equivalents of 1M HCl inether to precipitate the title product as a white solid dihydrochloridesalt (95 mg; 78%; M.P. 85°-100° C. (dec); LC-MS: 430 (MH⁺); anal.RP18-HPLC RT: 4.13 min.).

EXAMPLE 40(3-Ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl-ethoxy)-quinazolin-4-yl]-amineDihydrochloride

The title product from Example 30 (107 mg, 0.245 mmol) in DMF (2 mL) wastreated with morpholine (214 μL, 2.45 mmol) at 80° C. for 24 hours. Thereaction mixture was partitioned between CHCl₃ and saturated aqueousNaHCO₃. The organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product (168 mg) waschromatographed on silica using 7.5% methanol/CH₂Cl₂ to provide 65 mg ofpure title product as its free base. This white solid was dissolved in aminimum volume of CHCl₃, and titrated with 2 equivalents of 1M HCl inether to precipitate the title product as a white solid (88 mg; 59%;M.P. 115°-130° C. (dec); LC-MS: 449 (MH⁺); anal. RP18-HPLC RT: 4.00min.).

EXAMPLE 412-[4-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanolHydrochloride

The title product from Example 33 (149 mg, 0.354 mmol) in methanol (3mL) was treated with 5M aqueous KOH (0.25 mL). The mixture was stirredat 20° C. for 30 minutes before removing the solvent in vacuo. The solidresidue was washed with water to remove salts, and dried azeotropicallyby dissolution two times in acetonitrile and concentration in vacuo toafford 95 mg of title product as its free base. This material wasconverted to its HCl salt according to the method used in Example 28 (89mg; 61%; M.P. 190°-215° C. (dec); LC-MS: 380 (MH⁺); anal. RP18-HPLC RT:3.66 min.).

EXAMPLE 42 (6,7-Diethoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amineHydrochloride

6,7-Diethoxyquinazolin-4-one (120 mg, 0.512 mmol), triphenylphosphine(295 mg, 1.126 mmol) and 3 mL of carbon tetrachloride were refluxed for16 hours. The reaction mixture was concentrated in vacuo to a residuewhich was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline(66 mg, 0.563 mmol) and refluxed for 3 hours. The cooled reactionmixture was filtered to afford solid title product which was washed with10 mL of isopropyl alcohol and dried in vacuo at 70° C., 140 mg (75%);mp 269°-270° C.

EXAMPLE 43(6,7-Diethoxy-quinazolin-4-yl)-(3-ethynyl-2-methyl-phenyl)-amineHydrochloride

4-Chloro-6,7-diethoxyquinazoline (200 mg, 0.792 mmol) and3-(2′-trimethylsilylethynyl-2-methyl-aniline (168 mg, 0.871 mmol) in 4mL of tert-butyl alcohol was refluxed for 16 hours. The cooled reactionmixture was diluted with 5 mL of ethyl ether and filtered to affordsolid(6,7-diethoxy-quinazolin-4-yl)-(3-(2′-trimethylsilyl-ethynyl)-2-methyl-phenyl)-aminehydrochloride which was washed with 10 mL of ethyl ether and dried invacuo at 70° C. This material was desilated directly by treatment with 2mL of methanol containing 1 drop of water and 100 mg of potassiumcarbonate for 0.5 hours. The heterogeneous reaction mixture was filteredthrough Celite and vacuum evaporated to a residue which was dissolved inexcess 1N HCl in methanol, precipitated with ethyl ether, filtered anddried in vacuo at 70° C. to afford the title product; 160 mg (75%); mp258°-259.5° C.

EXAMPLE 44 (3-Ethynyl-phenyl)-(6-methyl-quinazolin-4-yl)-amineHydrochloride

6-Methyl-quinazolin-4-one (350 mg, 2.18 mmol) was added to a suspensionof polymer-supported triphenylphosphine (from Fluka, 3.63 g of about 3mmol P/g resin; 10.9 mmol) in a mixture of CCl₄ (3.35 g, 21.80 mmol) and1,2 dichloroethane (10 mL). The mixture was heated to 60° C. for 2 hoursand then the polymer was removed by filtration and washed withdichloroethane. The filtrate was collected in a flask containing3-ethynyl-aniline (0.644 g, 2.18 mmol) and concentrated to 5 mL byevaporation. After 4 hours reflux under N₂, followed by cooling to 20°C., the title product was collected by filtration (551 mg; 86%; M.P.256°-257° C.; LC-MS: 260 (MH⁺); anal. RP-HPLC RT: 4.41 min).

EXAMPLE 452-{2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethylsulfanyl}-propionicAcid Ammonium Salt

The title product of Example 34 (150 mg, 0.34 mmol) was added to asolution of thiolactic acid (100 μL, 1.14 mmol) and KOH (150 mg, 2.7mmol) in degassed DMF (5 mL)/H₂O (0.5 mL). The reaction mixture wasstirred at 50° C. under an atmosphere of N₂ for 72 hours and then cooledto room temperature. The pH of the mixture was adjusted to about 4.0with acetic acid and then partitioned between CHCl₃ and brine. Theorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by preparativeRP18 HPLC utilizing a gradient of 15% to 100% CH₃CN/pH 4.5, 50 mMammonium acetate followed by lyophilization of the appropriate purefractions to afford the title product (28 mg; 18%; M.P. 95°-103° C.(dec); LC-MS: 468 (MH⁺); anal. RP-HPLC RT: 3.57 min).

EXAMPLE 46{2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethylsulfanyl}-aceticAcid Ammonium Salt

The title product was prepared from the title product of Example34 andmercaptoacetic acid according to the method of Example 45. (3%; LC-MS:454 (MH⁺); anal. RP-HPLC RT: 3.37 min).

EXAMPLE 474-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-ol

This product was isolated as a more lipophilic product (by preparativeRP18 HPLC) from the reaction used to generate the title product ofExample 46 (5%; LC-MS: 336 (MH⁺); anal. RP-HPLC RT: 3.60 min).

EXAMPLE 48(3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-vinyloxy-quinazolin-4-yl]-amineand[6-(2-ethoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethnynl-phenyl)-amineHydrochloride

The title product of Example 30 (107 mg, 0.245 mmol) was treated withsodium ethoxide (0.582 mmol) in refluxing ethanol (3 mL) for 24 hours.The solvent was removed in vacuo and the product was isolated by flashchromatography on silica using 10% acetone/CH₂Cl₂ to provide 30 mg ofthe 6-vinyloxy product (33%; M.P. 113°-114° C.; LC-MS: 362 (MH⁺); anal.RP-HPLC RT: 4.84 min). The 6-(2-ethoxy-ethoxy) derivative eluted as amore polar product (45 mg) and was converted to its HCl salt accordingto the procedure described for Example28 (43%; M.P. 220°-225° C. (dec);LC-MS: 408 (MH⁺); anal. RP-HPLC RT: 4.35 min).

EXAMPLE 494-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-olHydrochloride

(3-Ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-vinyloxy-quinazolin-4-yl]-amine(20 mg; from Example 48) was hydrolyzed by treatment with 6MHCl/methanol (30:70; 3 mL) at 50° C. for 5 days. The solution wasconcentrated in vacuo, and the residue was partitioned between CHCl₃ andbrine at a pH of about 7. The organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle product as its free base (15 mg), which was converted to its HClsalt according to the procedure described for Example 28 (M.P. 135°-150°C. (dec); LC-MS: 336 (MH⁺); anal. RP-HPLC RT: 3.77 min).

EXAMPLE 501-{2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethyl}-1H-pyridin-4-oneHydrochloride

NaH (30 mg of 60% in mineral oil, 0.77 mmol) was added to anhydrous DMF(2.0 mL) followed by pyrid-4-one (79 mg, 0.83 mmol). The mixture wasstirred 40 minutes at 22° C. until all solids dissolved and theevolution of H₂ ceased. The title product of Example 34 (120 mg, 0.28mmol) and tetrabutylammonium iodide (15 mg) were added and the reactionmixture was stirred at 22° C. for 7 days under N₂. Additionalpyrid-4-one (79 mg) and NaH (30 mg of 60%) were dissolved in DMF (2 mL)and the solution was added to the reaction mixture. After another 4 daysstirring the mixture was partitioned between CHCl₃ and brine. Theorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by flash chromatography on silicautilizing 10% methanol/CH₂Cl₂ to afford 65 mg of the free base of thetitle product which was converted to the mono-hydrochloride saltaccording to the procedure described for Example 28 (66 mg; M.P.240°-248° C. (dec); LC-MS: 457 (MH⁺); anal. RP-HPLC RT: 3.23 min)

EXAMPLE 511-{2-[4-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethyl}-1H-pyridin-4-oneHydrochloride

The free base of this product was prepared from the title product ofExample 30 and the sodium salt of pyrid-4-one as described for Example50. The free base was isolated by flash chromatography with 15%methanol/CHCl₃ and converted to the title product according to theprocedure described for Example 28 (32%; M.P. 155°-168° C. (dec); LC-MS:457 (MH⁺); anal. RP-HPLC RT: 3.45 min).

EXAMPLE 52 (3-Ethynyl-phenyl)-(6-methoxy-quinazolin-4-yl)-amineHydrochloride

A 25 mM solution of 6-methoxy-3H-quinazolin-4-one in 1,2-dichloroethanewas added to polymer-supported triphenylphosphine (from Fluka, about 3mmol P/g polymer; 2.5 mol equiv) and carbon tetrachloride (100 moleequiv). The reaction mixture was heated, with shaking, at 60° C. for 21hours, cooled to 22° C., and a 30 mM solution of the 3-ethynylaniline(1.5 mole equiv) in t-butanol was added. The resulting mixture was thenheated, with shaking, at 60° C. for 18 hours followed by cooling to 22°C. The polymer was filtered off and washed twice with methanol. Themethanol washes were added to the filtrate and the solution wasconcentrated in vacuo to afford the title product (73%; LC-MS: 276(MH⁺); anal. RP18-HPLC RT: 5.82 min). For these cases the analyticalRP18-HPLC system consisted of a Waters 717 (trademark) autosampler,Waters 996 Photodiode Array Detector (trademark), and Waters 600quarternary solvent delivery system, and was controlled by Millennium(trademark) software. The aliquots of samples were chromatographed usinga linear gradient of 0% to 100% acetonitrile/0.2M ammonium acetatebuffer (pH 4.5) over ten minutes at a flow rate of 3 ml/min. using aPerkin-Elmer Pecosphere (trademark) (3 mm×3 cm) C18 column.

The compounds of Examples 53-94, as their hydrochloride salts, wereprepared in an analogous manner to that of Example 52 from theappropriate 3H-quinazolin-4-one derivative and 3-ethynyl-aniline:

HPLC Exam- % LC-MS RT ple Product Yield (MH+) (mins) 53(6-Chloro-quinazolin-4-yl)-(3- 60 280, 282 6.44 ethynyl-phenyl)-amine 54[7-Chloro-6-(2,5-dichloro- 51 456, 458 8.74phenylsulfanyl)-quinazolin-4-yl]- (3-ethynyl-phenyl)-amine 557-Chloro-4-(3-ethyl-phenylamino)- 12 305, 307 6.51quinazolin-6-carbonitrile 56 [6-Bromo-7-(4-chloro-phenoxy)- 28 450, 4528.05 quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 57[6-(4-Bromo-benzylsulfanyl)- 50 446, 448 7.99quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 58 (7-Bromo-6-methylsulfanyl-46 370, 372 6.99 quinazolin-4-yl)-(3-ethynyl- phenyl)-amine 59{7-Chloro-6-[4-(4-chloro- 82 514, 516 9.45 phenylsulfanyl)-phenoxy]-quinazolin-4-yl}-(3-ethynyl- phenyl)-amine 60 (3-Ethynyl-phenyl)-(7- 88354 7.40 phenylsulfanyl-quinazolin-4-yl)- amine 61(3-Ethynyl-phenyl)-(6-iodo- 64 372 6.81 quinazolin-4-yl)-amine 62(3-Ethynyl-phenyl)-(6- 53 314 6.73 0trifluoromethyl-quinazolin-4-yl)-amine 63 [7-Chloro-6-(4-(4-chloro- 78 406, 408 8.06phenoxy)-quinazolin-4-yl]-(3- ethynyl-phenyl)-amine 64[7-Chloro-6-(4-chloro- 68 422, 424 8.45phenylsulfanyl)-quinazolin-4-yl]- (3-ethynyl-phenyl)-amine 65[7-Chloro-6-(4-methoxy-phenoxy)- 88 402, 404 7.55quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 66[7-Chloro-6-(4-fluoro-phenoxy)- 80 390 7.61 quinazolin-4-yl]-(3-ethynyl-phenyl)-amine 67 [6-(4-Chloro-phenoxy)-quinazolin- 79 372, 374 7.664-yl]-(3-ethynyl-phenyl)-amine 68 7-Bromo-4-(3-ethynyl- 61 431, 433 6.44phenylamino)-quinazolin-6- sulfonic acid 69(6-Bromo-7-chloro-quinazolin-4- 80 358, 360 7.17yl0-(3-ethynyl-phenyl)-amine 70 4-(3-Ethynyl-phenylamino)- 72 271 5.84quinazolin-6-carbonitrile 71 [6-(4-Bromo-phenylsulfanyl)-7- 70 466, 4688.56 chloro-quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 72{6-[2-(4-Bromo-phenoxy)- 79 478, 478 8.11ethylsulfanyl]-quinazolin-4-yl}-(3- ethynyl-phenyl)-amine 734-[7-Chloro-4-(3-ethynyl- 85 427, 429 7.56 phenylamino)-quinazolin-6-ylsulfanyl-methyl]-benzonitrile 74 [7-Chloro-6-(3-chloro-phenoxy)- 80406, 408 8.10 quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 75[6-(3-Bromo-phenoxy)-7-chloro- 82 450, 452 8.22quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 76(7-Chloro-6-phenoxy-quinazolin-4- 83 372, 374 7.59yl)-3-ethynyl-phenyl)-amine 77 [7-Chloro-6-(4-methylsulfanyl- 86 418,420 8.02 phenoxy)-quinazolin-4-yl]-(3- ethynyl-phenyl)-amine 78[7-Chloro-6-(4-methanesulfonyl- 73 450, 452 6.73phenoxy)-quinazolin-4-yl]-(3- ethynyl-phenyl)-amine 79(7-Chloro-6-p-tolyloxy-quinazolin- 85 386, 388 4.954-yl]-(3-ethynyl-phenyl)-amine 80 (e-Ethynyl-phenyl)-[6-(4-phenoxy- 81430 8.29 phenoxy)-quinazoin-4-yl]-amine 81 (7-Chloro-6-phenylsulfanyl-80 388, 390 7.96 quinazolin-4-yl)-(3-ethynyl- phenyl)-amine 82[6-(3-Chloro-phenoxy)-quinazolin- 77 372, 374 7.714-yl]-(3-ethynyl-phenyl)-amine 83 [6-(3,5-Dichloro-phenoxy)- 61 406, 4088.30 quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 84[6-(2-Chloro-phenoxy)-quinazolin- 70 372, 374 7.384-yl]-(3-ethynyl-phenyl)-amine 85 (7-Chloro-6-methanesulfonyl- 74 358,360 5.74 quinazooin-4-yl)-(3-ethynyl- phenyl)-amine 86[6-(3,4-Dichloro-phenoxy)- 62 406, 408 8.14 quinazolin-4-yl]-(3-ethynyl-phenyl)-amine 87 [6-(4-Bromo-phenoxy)-quinazolin- 68 416, 418 7.814-yl]-(3-ethynyl-phenyl)-amine 88 [6-(4-Chloro-2-methyl-phenoxy)- 73386, 388 8.02 quinazolin-4-yl]-(3-ethynyl- phenyl)-amine 89[7-Chloro-4-(3-ethynyl- 70 351 6.44 phenylamino)-quinazolin-6-ylsulfanyl]-acetonitrile** 90 (6-Allylsulfanyl-quinazolin-4-yl)- 72 3186.93 (3-ethynyl-phenyl)-amine 91 (7-Chloro-6-propylsulfanyl- 69 354, 3567.79 quinazolin-4-yl)-(3-ethynyl- phenyl)-amine 92(7-Chloro-6-methyl-sulfanyl- 72 326, 328 6.94quinazolin-4-yl)-(3-ethynyl- phenyl)-amine 93[7-Chloro-6-(2-methyl-sulfanyl- 71 386, 388 7.56ethylsulfanyl)-quinazolin-4-yl]-(3- ethynyl-phenyl)-amine 94(6-Chloro-7-methoxy-quinazolin-4- 87 310, 312 6.65yl)-(3-ethynyl-phenyl)-amine**[7-Chloro-4-(3-ethynyl-phenylamino)-quinazolin-6-ylsulfanyl]-acetonitrilewas obtained from2-(7-chloro-4-oxo-3,4-dihydro-quinazolin-6-ylsulfanyl)-acetamide underthese conditions.

EXAMPLE 95 (6,7-Dibutoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amineHydrochloride

6,7-Dibutoxyquinazolin-4-one (105 mg, 0.362 mmol), triphenylphosphine(208 mg, 0.796 mmol) and 5 mL of carbon tetrachloride were refluxed for16 hours and the reaction mixture was concentrated in vacuo to a residuewhich was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline(47 mg, 0.398 mmol) and refluxed for 3 hours. The cooled reactionmixture was filtered to afford solid(6,7-dibutoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloridewhich was washed with 10 mL of isopropyl alcohol and dried in vacuo at70° C., 92 mg (60%); mp 247°-248° C.

EXAMPLE 96 (6,7-Diisopropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amineHydrochloride

6,7-Diisopropoxyquinazolin-4-one (55 mg, 0.210 mmol), triphenylphosphine(121 mg, 0.462 mmol) and 3 mL of carbon tetrachloride were refluxed for16 hours and the reaction mixture was concentrated in vacuo to a residuewhich was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline(30 mg, 0.257 mmol) and refluxed for 3 hours. The cooled reactionmixture was vacuum evaporated to afford the solid title product whichwas column chromatographed on silica gel eluted with 5% acetone inmethylene chloride containing 0.25% triethylamine. Fractions containingthe pure product were concentrated in vacuo to a solid which wasdissolved in 2 mL of 1N HCl in methanol, precipitated with ethyl ether,filtered and dried in vacuo at 70° C. to afford the title product; 140mg (75%); mp 241°-242° C.

EXAMPLE 97(6-Chloro-7-(2-methoxyethylsulfanyl)-quinazolin-4-yl)-(3-ethynyl-phenyl)-amineHydrochloride

6-Chloro-7-(2-methoxyethylsulfanyl)-quinazolin-4-one (200 mg, 0.739mmol), triphenylphosphine (427 mg, 1.63 mmol) and 0.7 mL of carbontetrachloride were refluxed in 4 ml of 1,2-dichloroethane for 4 hours,concentrated in vacuo to a residue, diluted with 4 mL of isopropylalcohol and 3-ethynylaniline (129 mg, 1.104 mmol) and refluxed for 16hours. The hot reaction mixture was filtered to isolate crude productwhich was column chromatographed on silica gel eluted with 5% methanolin chloroform. Fractions containing the pure product were concentratedin vacuo to afford the title product as a solid; 23 mg (8.4%); mp230°-232° C.

EXAMPLE 98(6,7-Bis-[2-methoxyethoxy]-quinazolin-4-yl)-(3-ethynyl-2-methyl-phenyl)-amine

6,7-Bis-[2-methoxyethoxy]-4-chloro-quinazoline (90 mg, 0.288 mmol) and3-(2′-trimethylsilylethynyl-2-methyl-aniline (62 mg, 0.317 mmol) wererefluxed in 4 mL of tert-butyl alcohol for 16 hours. The cooled reactionmixture was diluted with 1 mL of isopropyl alcohol and filtered toafford solid(6,7-bis-(methoxyethoxy)-quinazolin-4-yl)-(3-(2′-trimethylsilyl-ethyn-1yl)-2-methyl-phenyl)-amine hydrochloride which was washed with 10 mL ofethyl ether and dried in vacuo at 70° C.; 70 mg. Of this material 51 mgwas desilated by treatment with in 3 mL of methanol containing 1 drop ofwater and 50 mg of potassium carbonate for 0.5 hours at roomtemperature. The heterogeneous reaction mixture was filtered throughcelite and vacuum evaporated to a residue which was dried in vacuo at70° C. to afford the title product as a dry foam; 38 mg (75%); mp 232°C.

EXAMPLE 99(6,7-Bis-[2-methoxyethoxy]-quinazolin-4-yl)-(3-ethynyl-5′-fluoro-phenyl)-amineHydrochloride

6,7-Bis[2-methoxyethoxy]-4-chloro-quinazoline (90 mg, 0.288 mmol) and3-(2′-trimethylsilylethynyl-5-fluoro-aniline (69 mg, 0.317 mmol) wererefluxed in 3 mL of tert-butyl alcohol for 5 hours. The cooled reactionmixture was diluted with 2 mL of isopropyl alcohol and filtered toafford solid(6,7-bis-methoxyethoxy-quinazolin-4-yl)-(3-(2′-trimethylsilyl-ethynyl)-5′-fluoro-phenyl)-aminehydrochloride which was washed with 10 mL of ethyl ether and dried invacuo at 70° C.; 131 mg. All of this material was desilated bydissolution in 3 mL of methanol containing 1 drop of water and 35 mg ofpotassium carbonate for 0.5 hours at room temperature. The reactionmixture was adjusted to pH 2.5 with aqueous 1N hydrochloric acid andfiltered. The solid was dried in vacuo at 70° C. to afford the titleproduct; 92 mg (78%); mp 249°-250° C.

EXAMPLE 100 (7-Propylsulfanyl-quinazolin-4-yl)-(3-ethynyl-phenyl)-amineHydrochloride

7-Propylsulfanyl-quinazolin-4-one (300 mg, 1.36 mmol),triphenylphosphine (785 mg, 2.99 mmol), 1.31 mL of carbon tetrachlorideand 5 mL of chloroform were refluxed for 16 hours and the reactionmixture was concentrated in vacuo to a residue which was diluted with 5mL of isopropyl alcohol and 3-ethynylaniline (175 mg, 1.49 mmol) andrefluxed for 3 hours. The cooled reaction mixture was concentrated invacuo and the residue purified by column chromatography on silica geleluted with 10% methanol in chloroform. Fractions containing the puretitle product, as the frree amine, were concentrated in vacuo to affordsolid which was added to 3 mL of 1N HCl in methanol. This solution wasevaporated in vacuo to a residue which was triturated with 4 mL of hotisopropyl alcohol cooled and filtered. The solid thus obtained was driedin vacuo at 70° C. to afford pure title product; 239 mg (55%); mp229°-230° C.

EXAMPLE 101[7-(2-Methoxyethylsulfanyl)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amineHydrochloride

In the same manner as Example 42[7-(2-methoxyethylsulfanyl)-quinazolin-4-yl]-(3-ethynyl-phenyl)-aminehydrochloride was prepared from7-(2-methoxyethylsulfanyl)-quinazolin-4-one (200 mg, 0.847 mmol),triphenylphosphine (533 mg, 2.03 mmol) and 3 mL of carbon tetrachloridein 74% yield; 233 mg; mp 208°-209° C.

EXAMPLE 102 (7-Chloro-6-nitro-quinazolin-4-yl)-(3-ethynyl-phenyl)-amineHydrochloride

7-Chloro-6-nitro-quinazolin-4-one (1.002 g, 4.44mmol), phosphorousoxychloride (11.5 g, 7.51 mmol) and phosphorous pentachloride (1.62 g,7.74 mmol) were refluxed for 2 hours and the reaction mixture wasconcentrated in vacuo to a residue which was triturated with toluene andthen again with chloroform and dried in vacuo to afford crude4,7-dichloro-6-nitro-quinazoline. This was dissolved in 35 mL ofisopropyl alcohol and 3-ethynylaniline (639 mg, 5.45 mmol) and refluxedfor 3 hours. The cooled reaction mixture was filtered to afford thetitle product as a solid which was washed with 10 mL of isopropylalcohol and dried in vacuo at 70° C., 1.055 g (66%); mp 230.8°-232.6° C.

EXAMPLE 103 (6-Amino-7-chloro-quinazolin-4-yl)-(3-ethynyl-phenyl)-amineHydrochloride

(7-Chloro-6-nitro-quinazolin-4-yl)-(3-ethynyl-phenyl)-aminehydrochloride (166 mg, 0.295 mmol) and sodium dithionite (207 mg, 1.19mmol) were stirred in 1.5 mL of formic acid for 4 hours at roomtemperature. 45 mL of methanol were added to the reaction mixture whichwas set aside for 16 hours at room temperature. The precipitate thusobtained was filtered, triturated with 3% sodium bicarbonate for 0.5hours and refiltered. The solid was dissolved in 20 mL of 1N HCl inmethanol and precipitated with 200 mL of ethyl ether. This was filteredand dried in vacuo at 70° C. to afford the title product, 72 mg (83%);mp 260°-265° C.

EXAMPLE 104 (3-Ethynyl-phenyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine

(7-Chloro-6-nitroquinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride(100 mg, 0.306 mmol and dry sodium methoxide (120 mg, 2.22 mmol) werestirred in 2 mL of dry 2-methylpyrrolidin-1-one for 8 hours at 30° C. Tothe cooled reaction mixture 0.93 mL of 3N and 1 mL of water were added.The mixture was diluted with 60 mL of water and extracted with two time60 mL of ethyl acetate. The pooled organic layers were washed with threetimes 50 mL of water and 50 mL of brine, dried with magnesium sulfate,filtered and vacuum evaporated to afford the title product as a solid;80 mg (82%); mp 213°-218° C. dec.

EXAMPLE 105{2-[4-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethylsulfanyl}-aceticAcid Ammonium Salt

This product was prepared from the title product of Example 30 andmercaptoacetic acid at 22° C. over 10 days according to the methodoutlined in Example 45. (16%; M.P. 98°-113° C. (dec); LC-MS 454 (MH⁺);anal. RP-HPLC 3.24 min.)

PREPARATION 1 6,7-Bis(2-methoxy-ethoxy)-quinazolone

To ethyl 3,4-dihydroxybenzoate (36.4 g, 0.200 mol), K₂CO₃ (60.8 g, 0.44mol) and tetrabutylammonium iodide (750 mg) in degassed acetone (400 mL)was added 2-bromoethyl methyl ether (69.5 g, 47 mL). The mixture wasstirred under N₂ at reflux for 64 hours. Ether (600 mL) was added to themixture and after stirring 30 minutes at 20° C. the precipitated saltswere removed by filtration. The filtrate was concentrated in vacuo andthe residue was triturated with hexane (500 mL) for 30 minutes and thewhite solid ethyl 3,4-bis(2-methoxy-ethoxy)benzoate was filtered anddried in vacuo (55.5 g; 93%; M.P. 50°-51° C.). A portion of this product(45.7 g, 0.158 mol) in acetic acid (150 mL) was treated dropwise withconc. HNO₃ (40 mL) at 5° C. and the solution stirred 24 hours beforepouring into cold H₂O (1.6 L). The mixture was extracted with ethylacetate (1.1 L), and the organic phase was washed three times with 200mL H₂O, and brine, dried over Na₂SO₄, filtered and concentrated in vacuoto afford ethyl 4,5-bis-(2-methoxy-ethoxy)-2-nitro-benzoate (54.3 g) asa brown oil. This nitro product (52.0 g, 0.15 mol) was dissolved inethanol (1000 mL) containing 1 equivalent of HCl (generated in theethanol by prior addition of 11 mL acetyl chloride), PtO₂.H₂O (1.0 g)was added, and the mixture was hydrogenated under 45 psi H₂ for 6 hours.The catalyst was removed by filtration through Celite, and the filtratewas concentrated in vacuo to a thick slurry which was diluted with ether(400 mL). The solid white hydrochloride salt of ethyl2-amino-4,5-bis-(2-methoxy-ethoxy)benzoate was filtered and dried invacuo (44.7 g; 88%). A portion of this material (42 g, 0.12 mol) andammonium formate (7.6 g, 0.12 mol) were dissolved in formamide (63 mL)and the stirred mixture was heated to 160°-165° C. under an atmosphereof N₂ for 3 hours. H₂O (200 mL) was added and after cooling theprecipitated crude title product was recovered by filtration, washedwith cold H₂O, and dried in vacuo. The filtrate was extracted five timeswith CHCl₃, and the pooled organic extracts were washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The residue and crudequinazolone precipitate were combined, triturated in hot acetonitrile(250 mL) for 30 minutes, cooled to 20° C. and treated with ether (250mL). After cooling to 4° C. the white solid was filtered and dried invacuo (30.4 g, 86%; GC-MS m/z 294 (M⁺)).

PREPARATION 2 4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline

To 6,7-bis(2-methoxy-ethoxy)-quinazolone (500 mg, 1.7 mmol), fromPreparation 1, in CHCl₃ (10 mL) containing one drop of DMF was addedoxalylchloride (490 μL, 5.6 mmol) in several portions over 5 minutes.Once foaming ceased the solution was refluxed 1.5 hours. The solvent wasremoved in vacuo and the residue was dissolved in 1,2-dichloroethane (20mL) and washed two times with 80 mL saturated aqueous Na₂CO₃. Theorganic phase was dried over Na₂SO₄, and concentrated in vacuo to affordsolid title product (520 mg, 92%; M.P. 108°-109° C.).

PREPARATION 3 4-Chloro-6,7-bis-(2-chloro-ethoxy)-quinazoline,4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazoline and4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline and4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline

6,7-Bis(2-methoxy-ethoxy)-quinazolone (5.4 g, 18.3 mmol), fromPreparation 1, and pyridine (3.0 mL, 37 mmol) were heated in refluxingPOCl₃ (22 mL) under an atmosphere of dry nitrogen for 2.5 hours.Following concentration of the mixture in vacuo at 60° C. the residuewas dissolved in CHCl₃ (150 mL) and carefully added in portions withstirring to cold saturated aqueous NaHCO₃ (100 mL). The mixture wasstirred 10 min. after the addition was complete and the organic phasewas separated, washed with brine, dried over Na₂SO₄, and concentrated invacuo. The residue was flash chromatographed on silica using a gradientof 20% to 60% ethyl acetate/hexanes to afford 3.41 g of4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 234 mg of4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazoline, 532 mg of4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline, and 330mg of 4-chloro-6,7-bis-(2-chloroethoxy)-quinazoline.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein: m is 1, 2, or 3;each R¹ is independently selected from the group consisting of hydrogen,halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano,trifluoromethyl, and -(C₁-C₄ alkylene)-W-(phenyl) wherein W is a singlebond, O, S or NH; or each R¹ is independently selected from R⁹ andC₁-C₄-alkyl substituted by cyano, wherein R⁹ is selected from the groupconsisting of R⁵, —OR⁶, —NR⁶R⁶, —C(O)R⁷, —NHOR⁵, —OC(O)R⁶, cyano, A and—YR⁵; R⁵ is C₁-C₄ alkyl; R⁶is independently hydrogen or R⁵; R⁷ is R⁵,—OR⁶ or —NR⁶R⁶; A is selected from piperidino, morpholino, pyrrolidino,4-R⁶-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C₁-C₄ alkylene)(CO₂H), phenoxy, phenyl, phenylsulfanyl, C₂-C₄ alkenyl, and -(C₁-C₄alkylene)C(O)NR⁶R⁶; and Y is S, SO, or SO₂; wherein the alkyl moietiesin R⁵, —OR⁶ and —NR⁶R⁶ are optionally substituted by one to three halosubstituents and the alkyl moieties in R⁵, —OR⁶ and —NR⁶R⁶ areoptionally substituted by 1 or 2 R⁹ groups, and wherein the alkylmoieties of said optional substituents are optionally substituted byhalo or R⁹, with the proviso that two heteroatoms are not attached tothe same carbon atom; or each R¹ is independently selected from—NHSO₂R⁵, phthalimido-(C₁-C₄) -alkylsulfonylamino, benzamido,benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl,2,5-dioxopyrrolidin-1-yl, and R¹⁰-(C₂-C₄) -alkanoylamino wherein R¹⁰ isselected from halo, —OR⁶, C₂-C₄ alkanoyloxy, —C(O)R⁷, and —NR⁶R⁶; andwherein said —NHSO₂R⁵, phthalimido-(C₁-C₄-alkylsulfonylamino, benzamido,benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl,2,5-dioxopyrrolidin-1-yl, and R¹⁰-(C₂-C₄)-alkanoylamino R¹ groups areoptionally substituted by 1 or 2 substituents independently selectedfrom halo, C₁-C₄ alkyl, cyano, methanesulfonyl and C₁-C₄ alkoxy; or twoR¹ groups are taken together with the carbons to which they are attachedto form a 5-8 membered ring that includes 1 or 2 heteroatoms selectedfrom O, S and N; R² is hydrogen or C₁-C₆ alkyl optionally substituted by1 to 3 substituents independently selected from halo, C₁-C₄ alkoxy,—NR⁶R⁶, and —SO₂R⁵; n is 1 or 2 and each R³ is independently selectedfrom hydrogen, halo, hydroxy, C₁-C₆ alkyl, —NR⁶R⁶, and C₁-C₄ alkoxy,wherein the alkyl moieties of said R³ groups are optionally substitutedby 1 to 3 substituents independently selected from halo, C₁-C₄ alkoxy,—NR⁶R⁶, and —SO₂R⁵; and, R⁴ is azido or -(ethynyl)-R¹¹ wherein R¹¹ ishydrogen or C₁-C₆ alkyl optionally substituted by hydroxy, —OR⁶, or—NR⁶R⁶.
 2. The compound according to claim 1 wherein R² is hydrogen andR⁴ is -(ethynyl)-R¹¹.
 3. A pharmaceutical composition for the treatmentof a hyperproliferative disorder in a mammal which comprises apharmaceutically effective amount of the compound of claim 1 and apharmaceutically acceptable carrier.
 4. The compound of claim 1 whereineach R¹ is independently selected from hydrogen, hydroxy, hydroxyamino,nitro, carbamoyl, ureido, R⁵ optionally substituted with halo, —OR⁶,carboxy, or —C(O)NH₂; —OR⁵ optionally substituted with halo, —OR⁶,—OC(O)R⁶, —NR⁶R⁶, or A; —NR⁶R⁶, —C(O)NR⁶R⁶, —SR⁵, phenyl-(C₂-C₄)-alkoxywherein said phenyl moiety is optionally substituted with 1 or 2substituents independently selected from halo, R⁵ or —OR⁵.
 5. Thecompound according to claim 1 wherein R² is hydrogen and R⁴ is azido. 6.The compound of claim 1 wherein R³ is halo and R¹ is hydrogen or —OR⁵.7. The compound of claim 6 wherein R¹ is methoxy.
 8. The compound ofclaim 1 selected from the group consisting of:(6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;(6,7-dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine;[3-(2′-(aminomethyl)-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine;(3-ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine;(6,7-dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine;(6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine;(6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;(3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl)-amine;(3-ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amine;(6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-6-methylphenyl)-amine;(3-ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine;(3-ethynylphenyl)-[6-(4′-toluenesulfonylamino)quinazolin-4-yl]-amine;(3-ethynylphenyl)-{6-[2′-phthalimido-eth-1′-yl-sulfonylamino]quinazolin-4-yl}-amine;(3-ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine;(7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;(3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine;(6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;(7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine;(3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;(3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;(4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;(3-ethynylphenyl)-(6-methansulfonyl-quinazolin-4-yl)-amine;(6-ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine(6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;(6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1′-yl)-phenyl]-amine;[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amine;[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amine;[6,7-bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;[6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;[6,7-bis-(2-acetoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;2-[4-(3-ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanol;[6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;[7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;[7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;2-[4-(3-ethynyl-phenylamino)-6-(2-hydroxy-ethoxy)-quinazolin-7-yloxy]-ethanol;2-[4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanol;2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol;[6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;(3-ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine;(3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl)-ethoxy)-quinazolin-4-yl]-amine;(6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;(6,7-dibutoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;(6,7-diisopropoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;(6,7-diethoxyquinazolin-1-yl)-(3-ethynyl-2-methyl-phenyl)-amine;[6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynyl-2-methyl-phenyl)-amine;(3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;[6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;and2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol.that is [6,7-bis( 2 -methoxyethoxy)quinazolin- 4 -yl]-( 3-ethynylphenyl)-amine.
 9. The compound of claim 1 selected from thegroup consisting of(6,7-dipropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-phenyl)-amine;(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;(6,7-diethoxy-quinazolin-4-yl)-(5-ethynyl-2-methyl-phenyl)-amine;(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-methyl-phenyl)-amine;(6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;(6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylmethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylmethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;(6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;and(6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine.10. The compound of claim 1 selected from the group consisting of:(6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;(3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;[6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;[6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;(6,7-dimethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;(3-ethynylphenyl)-(6-methanesulfonylamino-quinazolin-1-yl)-amine; and,(6-amino-quinazolin-1-yl)-(3-ethynylphenyl)-amine.
 11. A pharmaceuticalcomposition for the treatment of a hyperproliferative disorder in amammal which comprises a therapeutically-effective amount of thecompound of claim 1 and a pharmaceutically acceptable carrier.
 12. Amethod of treating a hyperproliferative disorder in a mammal whichcomprises administering to said mammal a therapeutically-effectiveamount of the compound of claim
 1. 13. The method of claim 12 whereinsaid hyperproliferative disorder is cancer.
 14. The method of claim 13wherein said cancer is brain, lung, squamous cell, bladder, gastric,pancreatic, breast, head, neck, oesophageal, gynecological or thyroidcancer.
 15. The method of claim 12 wherein the hyperproliferativedisease is noncancerous.
 16. The method of claim 15 wherein saiddisorder is a benign hyperplasia of the skin or prostate.
 17. A processfor preparing a compound of the formula

or a pharmaceutically acceptable salt or prodrug thereof, wherein: m is1, 2, or 3; each R¹ is independently selected from the group consistingof hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino,ureido, cyano, trifluoromethyl, and -(C₁-C₄ alkylene)-W-(phenyl) whereinW is a single bond, O, S or NH; or each R¹ is independently selectedfrom R⁹ and (C₁-C₄)-alkyl substituted by cyano, wherein R⁹ is selectedfrom the group consisting of R⁵, —OR⁶, —NR⁶R⁶, —C(O)R⁷, —NHOR⁵,—OC(O)R⁶, cyano, A and —YR⁵; R⁵is C₁-C₄ alkyl; R⁶ is independentlyhydrogen or R⁵; R⁷ is R⁵, —OR⁶ or —NR⁶R⁶; A is selected from piperidino,morpholino, pyrrolidino, 4-R⁶-piperazin-1-yl, imidazol-1-yl,4-pyridon-1-yl, -(C₁-C₄ alkylene)(CO₂H), phenoxy, phenyl,phenylsulfanyl, C₂-C₄ alkenyl, and -(C₁-C₄ alkylene)C(O)NR⁶R⁶; and Y isS, SO, or SO₂; wherein the alkyl moieties in R⁵, —OR⁶ and —NR⁶R⁶ areoptionally substituted by one to three substituents independentlyselected from halo and R⁹, and wherein the alkyl moieties of saidoptional substituents are optionally substituted by halo or R⁹, with theproviso that two heteroatoms are not attached to the same carbon atom,and with the further proviso that no more than three R⁹ groups maycomprise a single R¹ group; or each R¹ is independently selected from—NHSO₂R⁵, phthalimido-(C₁-C₄)-alkylsulfonylamino, benzamido,benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl,2,5-dioxopyrrolidin-1-yl, and R¹⁰-(C₂-C₄)-alkanoylamino wherein R¹⁰ isselected from halo, —OR⁶, C₂-C₄ alkanoyloxy, —C(O)R⁷, and —NR⁶R⁶; andwherein the foregoing R¹ groups are optionally substituted by 1 or 2substituents independently selected from halo, C₁-C₄ alkyl, cyano,methanesulfonyl and C₁-C₄ alkoxy; or two R¹ groups are taken togetherwith the carbons to which they are attached to form a 5-8 membered ringthat includes 1 or 2 heteroatoms selected from O, S and N; R² ishydrogen or C₁-C₆ alkyl optionally substituted by 1 to 3 substituentsindependently selected from halo, C₁-C₄ alkoxy, —NR⁶R⁶, and —SO₂R⁵; n is1 or 2 and each R³ is independently selected from hydrogen, halo,hydroxy, C₁-C₆ alkyl, —NR⁶R⁶, and C₁-C₄ alkoxy, wherein the alkylmoieties of said R³ groups are optionally substituted by 1 to 3substituents independently selected from halo, C₁-C₄ alkoxy, —NR⁶R⁶, and—SO₂R⁵; and, R⁴ is azido or -(ethynyl)-R¹¹ wherein R¹¹ is hydrogen orC₁-C₆ alkyl optionally substituted by hydroxy, —OR⁶, or —NR⁶R⁶;  whichcomprises a) treating a compound of the formula

 wherein R¹ and m are as defined above, with CCl₄ and (C₆-C₁₀aryl)₃P,optionally supported on an inert polymer, wherein the aryl moieties ofsaid (C₆-C₁₀aryl)₃P are optionally substituted by C₁-C₆ alkyl; and b)treating the product of step a) with a compound of the formula

 wherein R², R³ and n are as defined above, and J is Y or R⁴, wherein R⁴is as defined above and wherein Y is NH₂, Br, I ortrifluoromethanesulfonyloxy, with the proviso that when J is Y then theproduct of step b) must further be treated with an alkyne where Y is Br,I or trifluoromethanesulfonyloxy, or an azide where Y is NH₂.
 18. Theprocess of claim 17 wherein each aryl group is selected from phenyl,naphth-1-yl and naphth-2-yl.
 19. The process of claim 17 wherein each Arin (C₆-C₁₀aryl)₃P is phenyl.
 20. The process of claim 17 wherein said(C₆-C₁₀aryl)₃P is supported on an inert polymer.
 21. The process ofclaim 20 wherein said inert polymer is a divinylbenzene-cross-linkedpolymer of styrene.
 22. The composition of claim 3 wherein saidhyperproliferative disorder is cancer.
 23. The composition of claim 22wherein said cancer is selected from the group consisting of renal,liver, kidney, colorectal, brain, lung, skin, bladder, gastric,pancreatic, breast, head, neck, oesophageal, vulval, gynecological, andthyroid cancer.
 24. The composition of claim 3 wherein saidhyperproliferative disorder is benign.
 25. The composition of claim 24wherein said hyperproliferative disorder is benign hyperplasia of theskin or prostate.
 26. The composition of claim 25 wherein saidhyperproliferative disorder is A pharmaceutical composition for thetreatment of psoriasis in a mammal which comprises a therapeuticallyeffective amount of the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 27. A method of treating a hyperproliferativedisorder in a mammal which comprises administering to said mammal apharmaceutically effective amount of the compound of claim
 1. 28. Themethod of claim 27 wherein said hyperproliferative disorder is cancer.29. The method of claim 28 wherein said cancer is selected from thegroup consisting of renal, liver, kidney, colorectal, brain, lung, skin,bladder, gastric, pancreatic, breast, head, neck, oesophageal, vulval,gynecological, and thyroid cancer.
 30. The method of claim 27 whereinsaid hyperproliferative disorder is benign.
 31. The method of claim 30wherein said hyperproliferative disorder is benign hyperplasia of theskin or prostate.
 32. The method of claim 31 wherein saidhyperproliferative disorder is A method of treating psoriasis in amammal which comprises administering to said mammal a therapeuticallyeffective amount of the compound of claim
 1. 33. A pharmaceuticalcomposition for the treatment of psoriasis in a mammal which comprises atherapeutically effective amount of the compound of claim 8 and apharmaceutically acceptable carrier.
 34. A compound that is apharmaceutically acceptable salt of [6,7-bis( 2-methoxyethoxy)quinazolin- 4 -yl]-( 3 -ethynylphenyl)-amine.
 35. Acompound that is a hydrochloride salt of [6,7-bis( 2-methoxyethoxy)quinazolin- 4 -yl]-( 3 -ethynylphenyl)-amine.